Can the recent sex-specific evolutions in elite running performances be attributed to advanced footwear technology?

Recent improvements in elite running performances across all distances have been largely attributed to the introduction of advanced footwear technology (AFT), which features a curved and stiff plate working synergistically with a new generation of midsole foams demonstrating enhanced resilience and compliance. These recent improvements appear to be considerably more pronounced in women's events, highlighted by improvements in road racing world records by an average of 3.7% (range: 2.6%-5.2%) compared to mean progressions of 1.5% (range: 1.3%-1.9%) in the same men's events. Although there is a growing body of research investigating the mechanisms underpinning running performance enhancements derived from AFT, there remains no explanation for potential sex-based differences in their benefits. We overview the currently available evidence and highlight why the recent direction of AFT research provides a barrier to progress by focusing primarily on male athletes. We subsequently provide our perspective on why women may be benefiting from the new generation of shoes more than men, suggest potential mechanisms leading to hypotheses that need to be further investigated in upcoming studies, and finally propose that factors outside of footwear innovation may have concurrently driven the recently observed performance evolutions.

Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration.

Remyelination failure in diseases like multiple sclerosis (MS) was thought to involve suppressed maturation of oligodendrocyte precursors; however, oligodendrocytes are present in MS lesions yet lack myelin production. We found that oligodendrocytes in the lesions are epigenetically silenced. Developing a transgenic reporter labeling differentiated oligodendrocytes for phenotypic screening, we identified a small-molecule epigenetic-silencing-inhibitor (ESI1) that enhances myelin production and ensheathment. ESI1 promotes remyelination in animal models of demyelination and enables de novo myelinogenesis on regenerated CNS axons. ESI1 treatment lengthened myelin sheaths in human iPSC-derived organoids and augmented (re)myelination in aged mice while reversing age-related cognitive decline. Multi-omics revealed that ESI1 induces an active chromatin landscape that activates myelinogenic pathways and reprograms metabolism. Notably, ESI1 triggered nuclear condensate formation of master lipid-metabolic regulators SREBP1/2, concentrating transcriptional co-activators to drive lipid/cholesterol biosynthesis. Our study highlights the potential of targeting epigenetic silencing to enable CNS myelin regeneration in demyelinating diseases and aging.

Corrigendum: Safe and effective delivery of supplemental iron to healthy adults: a two-phase, randomized, double-blind trial - the safe iron study.

[This corrects the article DOI: 10.3389/fnut.2023.1230061.].

Fecal microbiota transplanted from old mice promotes more colonic inflammation, proliferation, and tumor formation in azoxymethane-treated A/J mice than microbiota originating from young mice.

Aging is a strong risk factor for colorectal cancer (CRC). It is well established that gut microbial dysbiosis can play a role in the etiology of CRC. Although the composition of the gut microbial community changes with age and is reported to become more pro-inflammatory, it is unclear whether such changes are also pro-tumorigenic for the colon. To address this gap, we conducted fecal microbiota transplants (FMT) from young (DY, ~6 wk) and old (DO, ~72 wk) donor mice into young (8 wk) recipient mice that were pre-treated with antibiotics. After initiating tumorigenesis with azoxymethane, recipients were maintained for 19 wk during which time they received monthly FMT boosters. Compared to recipients of young donors (RY), recipients of old donors (RO) had an approximately 3-fold higher prevalence of histologically confirmed colon tumors (15.8 vs 50%, Chi2 P = .03), approximately 2-fold higher proliferating colonocytes as well as significantly elevated colonic IL-6, IL-1ß and Tnf-α. Transcriptomics analysis of the colonic mucosa revealed a striking upregulation of mitochondria-related genes in the RO mice, a finding corroborated by increased mitochondrial abundance. Amongst the differences in fecal microbiome observed between DY and DO mice, the genera Ruminoclostridium, Lachnoclostridium and Marvinbryantia were more abundant in DY mice while the genera Bacteroides and Akkermansia were more abundant in DO mice. Amongst recipients, Ruminoclostridium and Lachnoclostridium were higher in RY mice while Bacteroides was higher in RO mice. Differences in fecal microbiota were observed between young and old mice, some of which persisted upon transplant into recipient mice. Recipients of old donors displayed significantly higher colonic proliferation, inflammation and tumor abundance compared to recipients of young donors. These findings support an etiological role for altered gut microbial communities in the increased risk for CRC with increasing age and establishes that such risk can be transmitted between individuals.

The potential impact of advanced footwear technology on the recent evolution of elite sprint performances.

Background: Elite track and field sprint performances have reached a point of stability as we near the limits of human physiology, and further significant improvements may require technological intervention. Following the widely reported performance benefits of new advanced footwear technology (AFT) in road-running events, similar innovations have since been applied to sprint spikes in hope of providing similar performance enhancing benefits. However, it is not yet clear based on current evidence whether there have been subsequent improvements in sprint performance. Therefore, the aims of this study were to establish if there have been recent year-to-year improvements in the times of the annual top 100 and top 20 athletes in the men's and women's sprint events, and to establish if there is an association between the extensive use of AFT and potential recent improvements in sprint performances. Methods: For the years 2016-19 and 2021-2022, the season best performances of the top 100 athletes in each sprint event were extracted from the World Athletics Top lists. Independent t-tests with Holm corrections were performed using the season's best performance of the top 100 and top 20 athletes in each year to identify significant differences between years for each sprint discipline. Following the classification of shoes worn by the top 20 athletes in each event during their annual best race (AFT or non-AFT), separate linear mixed-model regressions were performed to determine the influence of AFT on performance times. Results: For the top 100 and top 20 athletes, there were no significant differences year-to-year in any sprint event prior to the release of AFT (2016-2019). There were significant differences between AFT years (2021 or 2022) and pre-AFT years (2016-2019) in eight out of 10 events. These differences ranged from a 0.40% improvement (men's 100 m) to a 1.52% improvement (women's 400 m hurdles). In the second analysis, multiple linear mixed model regressions revealed that the use of AFT was associated with improved performance in six out of ten events, including the men's and women's 100 m, women's 200 m, men's 110 m hurdles, women's 100 m hurdles and women's 400 m hurdles (estimate range: -0.037 - 0.521, p = <0.001 - 0.021). Across both analyses, improvements were more pronounced in women's sprint events than men's sprint events. Conclusion: Following a period of stability, there were significant improvements in most sprint events which may be partly explained by advances in footwear technology. These improvements appear to be mediated by event, sex and potentially level of athlete.

Protein binding assays for an accurate differentiation of vitamin B12 from its inactive analogue. A study on edible cricket powder.

Inactive analogues of vitamin B12 (cobalamin, Cbl) can mimic the active Cbl in food if using the traditional microbiological measurements. Thus, overestimated Cbl was recently revealed in edible insects employing immunoaffinity adsorption, HPLC-separation and mass spectrometry (https://doi.org/10.1016/j.foodchem.2021.129048). Here we demonstrate the utility of a convenient binding assay to evaluate Cbl in edible cricket powders. The assay employed the Cbl-specific protein intrinsic factor (IF) and the analogue-detecting protein haptocorrin. The excessive analogues had a weak affinity for IF, resulting in a modest overestimate of Cbl. This overestimate was corrected by a novel mathematical procedure, based on the ratio of analogue/Cbl in the sample and their relative affinities for IF. We found that 100 g of cricket powders contained 40-60 µg of analogues and 0.75-2.2 µg of Cbl. This result was confirmed by HPLC. A correct approach to Cbl-measurements is essential for nutritional assessment of any analogue-containing food.

Safe and effective delivery of supplemental iron to healthy adults: a two-phase, randomized, double-blind trial - the safe iron study.

Introduction: The safety of novel forms of iron in healthy, iron-replete adults as might occur if used in population-based iron supplementation programs was examined. We tested the hypotheses that supplementation with nanoparticulate iron hydroxide adipate tartrate (IHAT), an iron-enriched Aspergillus oryzae product (ASP), or ferrous sulphate heptahydrate (FS) are safe as indicated by erythrocyte susceptibility to malarial infection, bacterial proliferation, and gut inflammation. Responses to FS administered daily or weekly, and with or without other micronutrients were compared. Methods: Two phases of randomized, double-blinded trials were conducted in Boston, MA. Phase I randomized 160 volunteers to six treatments: placebo, IHAT, ASP, FS, and FS plus a micronutrient powder (MNP) administrated daily at 60 mg Fe/day; and FS administered as a single weekly dose of 420 mg Fe. Phase II randomized 86 volunteers to IHAT, ASP, or FS administered at 120 mg Fe/day. Completing these phases were 151 and 77 participants, respectively. The study was powered to detect effects on primary endpoints: susceptibility of participant erythrocytes to infection by Plasmodium falciparum, the proliferation potential of selected pathogenic bacteria in sera, and markers of gut inflammation. Secondary endpoints for which the study was not powered included indicators of iron status and gastrointestinal symptoms. Results: Supplementation with any form of iron did not affect any primary endpoint. In Phase I, the frequency of gastrointestinal symptoms associated with FS was unaffected by dosing with MNP or weekly administration; but participants taking IHAT more frequently reported abdominal pain (27%, p < 0.008) and nausea (4%, p = 0.009) than those taking FS, while those taking ASP more frequently reported nausea (8%, p = 0.009). Surprisingly, only 9% of participants taking IHAT at 120 mg Fe/day (Phase II) reported abdominal pain and no other group reported that symptom. Discussion: With respect to the primary endpoints, few differences were found when comparing these forms of iron, indicating that 28 days of 60 or 120 mg/day of IHAT, ASP, or FS may be safe for healthy, iron-replete adults. With respect to other endpoints, subjects receiving IHAT more frequently reported abdominal pain and nausea, suggesting the need for further study. Clinical Trial Registration: ClinicalTrials.gov, NCT03212677; registered: 11 July 2017.

Which trunk muscle parameter is the best predictor for physical function in older adults?

Background: Despite preliminary evidence demonstrating the relevance of trunk muscle strength for physical function in older adults, it is not clear which muscle-related trunk parameter is the best predictor for physical functions. Therefore, this study aimed to compare trunk muscle morphology or strength parameters regarding their predictive ability for physical functions. Methods: Seventy-four older adults (38 men, 36 women, mean age 76.85 years) were tested for maximum absolute and relative isokinetic trunk flexion and extension strength, trunk lean mass, and trunk muscle quality. Functional assessment included normal and fast walking speed, repeated sit-to-stand transfer, timed up and go, and postural sway during a closed-feet and a semi-tandem stance adjusted for body height. Pearson's correlations were used to compare relationship between trunk strength adjusted and unadjusted for body weight to physical functions. Linear regression analysis including sex and age as co-variables was performed between trunk muscle and functional test parameters. Results: Relative back extension strength was the most consistent significant predictor for all physical function tests (p = 0.004-0.04) except for postural sway. Relative trunk flexion strength was related to normal walking speed (p = 0.024). Trunk lean mass was related to timed up and go performance (p = 0.024). Conclusion: Relative back extension strength is associated with better performance in nearly all standard tests for physical function in older adults, while trunk flexion strength and lean mass seem to play a minor role. Our findings emphasize the importance of trunk muscle strength, especially the back extensor muscles, for physical function in older adults.

Asymmetries of foot strike patterns during running in high-level female and male soccer players.

BACKROUND: Foot strike pattern (FSP) is defined by the way the foot makes initial ground contact and is influenced by intrinsic and extrinsic factors. This study investigated the effect of running speed on asymmetries of FSP. METHODS: Seventeen female and nineteen male soccer players performed an incremental running test on an instrumented treadmill starting at 2.0 m/s until complete exhaustion. Force plate data were used to categorize foot strikes into rearfoot (RFS) and non-rearfoot strikes. Additionally, peak vertical ground reaction force (peakGRF) and stride time were calculated. The symmetry index (SI) was used to quantify lateral asymmetries between legs. RESULTS: The SI indicated asymmetries of the rate of RFS (%RFS) of approximately 30% at slow running speed which decreased to 4.4% during faster running speed (p = 0.001). There were minor asymmetries in peakGRF and stride time at each running stage. Running speed influenced %RFS (p < 0.001), peakGRF (p < 0.001) and stride time (p < 0.001). Significant interaction effects between running speed and sex were shown for %RFS (p = 0.033), peakGRF (p < 0.001) and stride time (p = 0.041). CONCLUSION: FSP of soccer players are asymmetric at slower running speed, but symmetry increases with increasing speed. Future studies should consider that FSP are non-stationary and influenced by running speed but also differ between legs.

Tumor necrosis factor-α knockout mitigates intestinal inflammation and tumorigenesis in obese Apc1638N mice.

Strong evidence from observational studies shows that having body fatness is associated with an individual's risk of developing colorectal cancer (CRC), but the causality between obesity and CRC remains inadequately elucidated. Our previous studies have shown diet-induced obesity is associated with elevated TNF-α and enhanced activation of Wnt-signaling, yet the causal role of TNF-α on intestinal tumorigenesis has not been precisely studied. The present study aims to examine the functionality of TNF-α in the development of CRC associated with obesity. We first examined the extent to which diet-induced obesity elevates intestinal tumorigenesis by comparing Apc1638N mice fed a low fat diet (LFD, 10 kcal% fat) with those fed a high fat diet (HFD, 60 kcal% fat), and then investigated the degree that the genetic ablation of TNF-α attenuates the effect by crossing the TNF-α-/- mice with Apc1638N mice and feeding them with the same HFD (TNF-α KO HFD). After 16-weeks of feeding, the HFD significantly increased intestinal tumorigenesis, whereas the deletion of TNF-α attenuated the effect (P < .05). Accompanying the changes in macroscopic tumorigenesis, HFD significantly elevated intestinal inflammation and procarcinogenic Wnt-signaling, whereas abolishment of TNF-α mitigated the magnitude of these elevations (P < .05). In summary, our findings demonstrate that the knockout of TNF-α attenuates obesity-associated intestinal tumorigenesis by decreasing intestinal inflammation and thereby the Wnt-signaling, indicating that TNF-α signaling is a potential target that can be utilized to reduce the risk of CRC associated with obesity.

Intrinsic Risk Factors for Ankle Sprain Differ Between Male and Female Athletes: A Systematic Review and Meta-Analysis.

BACKGROUND: Ankle sprains remain prevalent across most team sports. However, despite divergent ankle sprain injury rates in male and female athletes, little is known about potential sex-specific risk factors for ankle sprain. OBJECTIVE: To systematically investigate the sex-specific risk factors for ankle sprain. METHODS: Combinations of the key terms were entered into PubMed, Web of Science, Embase and Cochrane Library databases, and prospective studies reporting ankle sprain risk factors in males or females were included for meta-analysis. RESULTS: Sixteen studies were eligible for inclusion, for a total of 3636 athletes (735 female) and 576 ankle sprains (117 female). Out of 21 prognostic factors, previous ankle sprain injury (odds ratio = 2.74, P < .001), higher body mass index (SMD = 0.50, P < 0.001), higher weight (SMD = 0.24, P = 0.02), lower isometric hip abduction strength (SMD = - 0.52, P < 0.0001) and lower dynamic balance performance (SMD = - 0.48 to - 0.22, P < 0.001-0.04) were identified as risk factors in male athletes. In female athletes, out of 18 factors eligible for meta-analysis, only lower concentric dorsiflexion strength was identified as a risk factor (SMD = - 0.48, P = 0.005). CONCLUSION: This meta-analysis provides novel evidence for different risk factor profiles for ankle sprain injuries between female and male athletes. Further studies, particularly in female athletes, are needed to strengthen the evidence.

Lipid Metabolism Is Dysregulated in the Motor Cortex White Matter in Amyotrophic Lateral Sclerosis.

Lipid metabolism is profoundly dysregulated in amyotrophic lateral sclerosis (ALS), yet the lipid composition of the white matter, where the myelinated axons of motor neurons are located, remains uncharacterised. We aimed to comprehensively characterise how myelin is altered in ALS by assessing its lipid and protein composition. We isolated white matter from the motor cortex from post-mortem tissue of ALS patients (n = 8 sporadic ALS cases and n = 6 familial ALS cases) and age- and sex-matched controls (n = 8) and conducted targeted lipidomic analyses, qPCR for gene expression of relevant lipid metabolising enzymes and Western blotting for myelin proteins. We also quantified myelin density by using spectral confocal reflectance microscopy (SCoRe). Whilst myelin protein composition was similar in ALS and control tissue, both the lipid levels and the expression of their corresponding enzymes were dysregulated, highlighting altered lipid metabolism in the white matter as well as a likely change in myelin composition. Altered myelin composition could contribute to motor neuron dysfunction, and this highlights how oligodendrocytes may play a critical role in ALS pathogenesis.

Chronic and Residual Effects of a Two-Week Foam Rolling Intervention on Ankle Flexibility and Dynamic Balance.

BACKGROUND: Foam rolling has been shown to acutely improve joint range of motion (ROM). However, limited knowledge exists on the chronic and residual effects. The primary purpose of this study was to examine the chronic and residual effects of a 2-week roller-massager intervention on ankle dorsiflexion ROM and dynamic balance. METHODS: Forty-two participants (24.3 ± 2.5 years, 33 males, 9 females) were randomly assigned to either roller-massage (RM) or control group (= no intervention). Ankle ROM was assessed with the weight-bearing lunge test (WBLT) and dynamic balance with the Y-Balance test for both limbs. The RM group was instructed to roll their calf muscles for three sets of 60 s per leg on 6 days a week over 2 weeks. Acute effects were measured during baseline testing for dorsiflexion ROM and dynamic balance immediately after foam rolling. Chronic and residual effects were measured 1 day and 7 days after the intervention period. Multivariate ANOVA was performed for post-hoc comparisons to determine acute, chronic, and residual effects. RESULTS: Significant acute and chronic foam rolling effects (p <0.05) were found for ankle dorsiflexion ROM. The chronic increase in ROM slightly decreased 7 days post-intervention but remained significantly above baseline (p < 0.05). Regarding dynamic balance, there were no acute but chronic (p < 0.05) and residual (p < 0.05) effects. CONCLUSION: Using a roller-massager for a 2-week period chronically increases ROM and dynamic balance. These increases are still significant 7 days post-intervention emphasizing the sustainability of foam rolling effects.

Maximum isometric torque at individually-adjusted joint angles exceeds eccentric and concentric torque in lower extremity joint actions.

BACKGROUND: Previous research indicates the high relevance of optimal joint angles for individual isometric strength assessment. The objective was to compare lower limb peak isometric muscle strength abilities at the strongest joint angles with those of dynamic contractions in healthy young adults. METHODS: Eighteen young male adults performed maximum concentric, isometric, and eccentric contractions of the ankle, knee, and hip flexors and extensors, and hip adductors and abductors in a randomized sequence on an isokinetic dynamometer (ISOMED 2000). Angular velocity was set at 60°/s. The peak of concentric contraction torque curves was used to define optimal joint angles best suited to generate maximum torque during isometric contractions. Maximum voluntary contraction torque of all contraction conditions was adjusted for limb weight and analyzed via a generalized linear mixed gamma regression model (GLMM). RESULTS: The gamma GLMM revealed strongly significant effects for all three categorical covariates (contraction types, muscle group, and test order) ([Formula: see text]). Eccentric contraction increases the muscle torque ([Formula: see text]) compared to concentric contraction, and isometric contraction even more ([Formula: see text]). A moderate individual-specific variation was found (random effects standard deviation [Formula: see text]). CONCLUSION: The results support the importance of optimal joint angles for isometric maximum strength assessment. When such conditions are given, isometric contractions can produce higher muscle torques than eccentric contractions in the lower body.

Tracking sleep in the field: sleep quality and sleep behaviours of elite track and field athletes during preparation and competition.

Elite athletes are susceptible to inadequate sleep, which may peak during competition and be exacerbated by poor sleep behaviours. This study sought to characterise and compare the sleep quality and sleep behaviours of elite track and field athletes during preparation and major competitions. Forty elite international track and field athletes (50% female, aged 25.1 ± 3.9 years) completed the Athlete Sleep Screening Questionnaire and the Athlete Sleep Behaviour Questionnaire on three separate occasions: during habitual training, during a pre-meet training camp and during a major international competition. Overall, 62.5% of athletes reported at least mild sleep difficulty during competition. Athletes reported higher sleep difficulty and poorer sleep behaviour during major competitions and the pre-meet training camp compared to habitual training (P = .001-.025). No significant differences were observed between the training camp and major competition. Global sleep behaviour scores were underpinned by unique characteristics at each timepoint. Sleep behaviour (R2 = .330, P = .017), injury status (R2 = .253, P = .003) and major championship experience (R2 = .113, P = .034) were associated with sleep difficulty during competition. Sleep quality and behaviours vary according to stage of the track and field season, providing a foundation for targeted intervention.

Perspective: The High-Folate-Low-Vitamin B-12 Interaction Is a Novel Cause of Vitamin B-12 Depletion with a Specific Etiology-A Hypothesis.

Vitamin B-12 is a water-soluble vitamin that plays important roles in intermediary metabolism. Vitamin B-12 deficiency has many identifiable causes, including autoimmune and other gastrointestinal malabsorption disorders, dietary deficiency, and congenital defects in genes that are involved in vitamin B-12 trafficking and functions. Another putative cause of vitamin B-12 deficiency is the high-folate-low vitamin B-12 interaction, first suspected as the cause for observed relapse and exacerbation of the neurological symptoms in patients with pernicious anemia who were prescribed high oral doses of folic acid. We propose that this interaction is real and represents a novel cause of vitamin B-12 depletion with specific etiology. We hypothesize that excessive intake of folic acid depletes serum holotranscobalamin (holoTC), thereby decreasing active vitamin B-12 in the circulation and limiting its availability for tissues. This effect is specific for holoTC and does not affect holohaptocorrin, the inert form of serum vitamin B-12. Depletion of holoTC by folic acid in individuals with already low vitamin B-12 status further compromises the availability of vitamin B-12 coenzymes to their respective enzymes, and consequently a more pronounced state of biochemical deficiency. This hypothesis is drawn from evidence of observational and intervention studies of vitamin B-12-deficient patients and epidemiological cohorts. The evidence also suggests that, in a depleted state, vitamin B-12 is diverted to the hematopoietic system or the kidney. This most likely reflects a selective response of tissues expressing folate receptors with high affinity for unmetabolized folic acid (UMFA; e.g., hematopoietic progenitors and renal tubules) compared with those tissues (e.g., liver) that only express the reduced folate carrier, which is universally expressed but has poor affinity for UMFA. The biochemical and physiological mechanisms underlying this interaction require elucidation to clarify its potential public health significance.

The Interval Between Matches Significantly Influences Injury Risk in Field Hockey.

Fixture congestion increases injury risk in football, but how it impacts other sports is unclear. The aim of this study was to identify associations between match density and injury incidence in field hockey players. Injury data from a prospective cohort study of professional and youth players was analysed in two ways. Inter-match intervals were clustered into<2424-hours, 3-7-days, and 13 + days, and injury rate ratios (IRR) were calculated to identify differences between clusters in match injuries. Separately, a Lasso-penalised Poisson regression model was used to determine the association between match load across the previous 24-hours, 3-days, 7-days and 14-days, and match and training injuries. Injury rates in matches within 24-hours of the previous match were mostly significantly higher when compared to matches after 3-7-days (IRRs: 3.78; 6.77, P = 0.003; 0.005). While a higher match exposure in the preceding 24-hour and 3-day periods was associated with higher combined match and training injury rates (ß̂ = 0.0001; 0.0018), a higher match exposure in the previous 7-and 14-day periods was associated with a reduced injury rate (ß̂ = -0.0001; -0.0005). Due to the increased injury risk in matches 3-days and especially 24-hours following the previous fixture, match distribution should be cautiously planned.

Multiple Dietary Vitamin K Forms Are Converted to Tissue Menaquinone-4 in Mice.

BACKGROUND: Vitamin K is a term that comprises a family of structurally related quinones, phylloquinone (PK) and the menaquinones (MKn), that share a common naphthoquinone ring but vary in sidechain length (n) and saturation. Dietary PK is a biosynthetic precursor to tissue menaquinone-4 (MK4), but little is known about the absorption and metabolism of dietary MKn. OBJECTIVE: To characterize the absorption and metabolism of dietary MKn relative to PK. METHODS: In the 4-week diet study, 10-week-old male and female C57BL/6 mice were pair-fed a vitamin K deficient diet (control) or a diet supplemented with 5.0 µmol/kg total PK, MK4, and/or MK9 (separately and in combination). In the 1-week stable isotope study, 12-week-old mice were pair-fed diets containing 2.2 µmol/kg PK (unlabeled control), 2H7PK, 13C11MK4, 2H7MK7, or 2H7MK9. Vitamin K tissue content was quantified by HPLC and/or LC-MS, and concentrations were compared by sex and diet group using 2-factor ANOVA. RESULTS: Regardless of the form(s) of vitamin K provided in the diet, tissue MK4 concentrations did not differ across equimolar supplemented groups in the kidney, adipose, reproductive organ, bone, or pancreas in either males or females in the diet study (all P values > 0.05). Isotopic labeling confirmed the naphthoquinone ring of MK4 in tissues originated from the administered dietary PK or MKn. Despite equimolar supplementation, accumulation of the administered dietary form differed across diet groups in small intestinal segments (all P values < 0.002) and the liver (P < 0.001). Female mice had greater total vitamin K than males in every tissue examined (P < 0.05). CONCLUSIONS: Dietary PK, MK4, MK7, and MK9 all served as precursors to tissue MK4 in mice. This study expands our understanding of vitamin K metabolism and supports a common conversion mechanism of all dietary vitamin K forms to MK4. Further investigation of the metabolism and physiological roles of MK4 that may be independent of classical vitamin K function is warranted.

Combined Supplementation with Vitamin B-6 and Curcumin is Superior to Either Agent Alone in Suppressing Obesity-Promoted Colorectal Tumorigenesis in Mice.

BACKGROUND: Obesity increases the colorectal cancer risk, in part by elevating colonic proinflammatory cytokines. Curcumin (CUR) and supplemental vitamin B-6 each suppress colonic inflammation. OBJECTIVES: We examined whether the combination of CUR and vitamin B-6 amplifies each supplement's effects and thereby suppress obesity-promoted tumorigenesis. METHODS: Male Friend Virus B (FVB) mice (4-week-old; n = 110) received 6 weekly injections of azoxymethane beginning 1 week after arrival. Thereafter, they were randomized to receive a low-fat diet (10% energy from fat), a high-fat diet (HFD; 60% energy from fat), a HFD containing 0.2% CUR, a HFD containing supplemental vitamin B-6 (24 mg pyridoxine HCl/kg), or a HFD containing both CUR and supplemental vitamin B-6 (C + B) for 15 weeks. Colonic inflammation, assessed by fecal calprotectin, and tumor metrics were the primary endpoints. The anti-inflammatory efficacy of the combination was also determined in human colonic organoids. RESULTS: HFD-induced obesity produced a 2.6-fold increase in plasma IL-6 (P < 0.02), a 1.9-fold increase in fecal calprotectin (P < 0.05), and a 2.2-fold increase in tumor multiplicity (P < 0.05). Compared to the HFD group, the C + B combination, but not the individual agents, decreased fecal calprotectin (66%; P < 0.01) and reduced tumor multiplicity and the total tumor burden by 60%-80% (P < 0.03) in an additive fashion. The combination of C + B also significantly downregulated colonic phosphatidylinositol-4,5-bisphosphate 3-kinase, Wnt, and NF-κB signaling by 31%-47% (P < 0.05), effects largely absent with the single agents. Observations that may explain how the 2 agents work additively include a 2.8-fold increased colonic concentration of 3-hydroxyanthranillic acid (P < 0.05) and a 1.3-fold higher colonic concentration of the active coenzymatic form of vitamin B-6 (P < 0.05). In human colonic organoids, micromolar concentrations of CUR, vitamin B-6, and their combination suppressed secreted proinflammatory cytokines by 41%-93% (P < 0.03), demonstrating relevance to humans. CONCLUSIONS: In this mouse model, C + B is superior to either agent alone in preventing obesity-promoted colorectal carcinogenesis. Augmented suppression of procancerous signaling pathways may be the means by which this augmentation occurs.