In vivo biodistribution and pharmacokinetics of sotrovimab, a SARS-CoV-2 monoclonal antibody, in healthy cynomolgus monkeys.

PURPOSE: Sotrovimab (VIR-7831), a human IgG1κ monoclonal antibody (mAb), binds to a conserved epitope on the SARS-CoV-2 spike protein receptor binding domain (RBD). The Fc region of VIR-7831 contains an LS modification to promote neonatal Fc receptor (FcRn)-mediated recycling and extend its serum half-life. Here, we aimed to evaluate the impact of the LS modification on tissue biodistribution, by comparing VIR-7831 to its non-LS-modified equivalent, VIR-7831-WT, in cynomolgus monkeys. METHODS: 89Zr-based PET/CT imaging of VIR-7831 and VIR-7831-WT was performed up to 14 days post injection. All major organs were analyzed for absolute concentration as well as tissue:blood ratios, with the focus on the respiratory tract, and a physiologically based pharmacokinetics (PBPK) model was used to evaluate the tissue biodistribution kinetics. Radiomics features were also extracted from the PET images and SUV values. RESULTS: SUVmean uptake in the pulmonary bronchi for 89Zr-VIR-7831 was statistically higher than for 89Zr-VIR-7831-WT at days 6 (3.43 ± 0.55 and 2.59 ± 0.38, respectively) and 10 (2.66 ± 0.32 and 2.15 ± 0.18, respectively), while the reverse was observed in the liver at days 6 (5.14 ± 0.80 and 8.63 ± 0.89, respectively), 10 (4.52 ± 0.59 and 7.73 ± 0.66, respectively), and 14 (4.95 ± 0.65 and 7.94 ± 0.54, respectively). Though the calculated terminal half-life was 21.3 ± 3.0 days for VIR-7831 and 16.5 ± 1.1 days for VIR-7831-WT, no consistent differences were observed in the tissue:blood ratios between the antibodies except in the liver. While the lung:blood SUVmean uptake ratio for both mAbs was 0.25 on day 3, the PBPK model predicted the total lung tissue and the interstitial space to serum ratio to be 0.31 and 0.55, respectively. Radiomics analysis showed VIR-7831 had mean-centralized PET SUV distribution in the lung and liver, indicating more uniform uptake than VIR-7831-WT. CONCLUSION: The half-life extended VIR-7831 remained in circulation longer than VIR-7831-WT, consistent with enhanced FcRn binding, while the tissue:blood concentration ratios in most tissues for both drugs remained statistically indistinguishable throughout the course of the experiment. In the bronchiolar region, a higher concentration of 89Zr-VIR-7831 was detected. The data also allow unparalleled insight into tissue distribution and elimination kinetics of mAbs that can guide future biologic drug discovery efforts, while the residualizing nature of the 89Zr label sheds light on the sites of antibody catabolism.

Wheat Germ Supplementation Reduces Inflammation and Gut Epithelial Barrier Dysfunction in Female Interleukin-10 Knockout Mice Fed a Pro-Atherogenic Diet.

BACKGROUND: Mice lacking IL-10 are prone to gut inflammation. Additionally, decreased production of short-chain fatty acids (SCFAs) plays a significant role in the high-fat (HF) diet-induced loss of gut epithelial integrity. We have previously shown that wheat germ (WG) supplementation increased ileal expression of IL-22, an important cytokine in maintaining gut epithelial homeostasis. OBJECTIVES: This study investigated the effects of WG supplementation on gut inflammation and epithelial integrity in IL-10 knockout mice fed a pro-atherogenic diet. METHODS: Eight-week-old female C57BL/6 wild type mice were fed a control diet (10% fat kcal), and age-matched knockout mice were randomly assigned to 1 of 3 diets (n = 10/group): control, high-fat high-cholesterol (HFHC) [(43.4% fat kcal (∼49% saturated fat, 1% cholesterol)], or HFHC + 10% WG (HFWG) for 12 wk. Fecal SCFAs and total indole, ileal, and serum proinflammatory cytokines, gene or protein expression of tight junctions, and immunomodulatory transcription factors were assessed. Data were analyzed by 1-way ANOVA, and P < 0.05 was considered statistically significant. RESULTS: Fecal acetate, total SCFAs, and indole increased (P < 0.05) by at least 20% in HFWG compared with the other groups. WG increased (P < 0.0001, 2-fold) ileal Il22 (interleukin 22) to Il22ra2 (interleukin 22 receptor, alpha 2) mRNA ratio and prevented the HFHC diet-mediated increase in ileal protein expression of indoleamine 2,3 dioxygenase and pSTAT3 (phosphorylated signal transducer and activator of transcription 3). WG also prevented the HFHC diet-mediated reduction (P < 0.05) in ileal protein expression of the aryl hydrocarbon receptor and the tight junction protein, zonula occludens-1. Serum and ileal concentrations of the proinflammatory cytokine, IL-17, were lower (P < 0.05) by at least 30% in the HFWG group than in the HFHC group. CONCLUSIONS: Our findings demonstrate that the anti-inflammatory potential of WG in IL-10 KO mice consuming an atherogenic diet is partly attributable to its effects on the IL-22 signaling and pSTAT3-mediated production of T helper 17 proinflammatory cytokines.

Extract of Artemisia dracunculus L. Modulates Osteoblast Proliferation and Mineralization.

Thiazolidinediones (TZD) significantly improve insulin sensitivity via action on adipocytes. Unfortunately, TZDs also degrade bone by inhibiting osteoblasts. An extract of Artemisia dracunculus L., termed PMI5011, improves blood glucose and insulin sensitivity via skeletal muscle, rather than fat, and may therefore spare bone. Here, we examine the effects of PMI5011 and an identified active compound within PMI5011 (2',4'-dihydroxy-4-methoxydihydrochalcone, DMC-2) on pre-osteoblasts. We hypothesized that PMI5011 and DMC-2 will not inhibit osteogenesis. To test our hypothesis, MC3T3-E1 cells were induced in osteogenic media with and without PMI5011 or DMC-2. Cell lysates were probed for osteogenic gene expression and protein content and were stained for osteogenic endpoints. Neither compound had an effect on early stain outcomes for alkaline phosphatase or collagen. Contrary to our hypothesis, PMI5011 at 30 µg/mL significantly increases osteogenic gene expression as early as day 1. Further, osteogenic proteins and cell culture mineralization trend higher for PMI5011-treated wells. Treatment with DMC-2 at 1 µg/mL similarly increased osteogenic gene expression and significantly increased mineralization, although protein content did not trend higher. Our data suggest that PMI5011 and DMC-2 have the potential to promote bone health via improved osteoblast maturation and activity.

Role of zinc transporter ZIP12 in susceptibility-weighted brain magnetic resonance imaging (MRI) phenotypes and mitochondrial function.

Brain zinc dysregulation is linked to many neurological disorders. However, the mechanisms regulating brain zinc homeostasis are poorly understood. We performed secondary analyses of brain MRI GWAS and exome sequencing data from adults in the UK Biobank. Coding ZIP12 polymorphisms in zinc transporter ZIP12 (SLC39A12) were associated with altered brain susceptibility weighted MRI (swMRI). Conditional and joint association analyses revealed independent GWAS signals in linkage disequilibrium with 2 missense ZIP12 polymorphisms, rs10764176 and rs72778328, with reduced zinc transport activity. ZIP12 rare coding variants predicted to be deleterious were associated with similar impacts on brain swMRI. In Neuro-2a cells, ZIP12 deficiency by short hairpin RNA (shRNA) depletion or CRISPR/Cas9 genome editing resulted in impaired mitochondrial function, increased superoxide presence, and detectable protein carbonylation. Inhibition of Complexes I and IV of the electron transport chain reduced neurite outgrowth in ZIP12 deficient cells. Transcriptional coactivator PGC-1α, mitochondrial superoxide dismutase (SOD2), and chemical antioxidants α-tocopherol, MitoTEMPO, and MitoQ restored neurite extension impaired by ZIP12 deficiency. Mutant forms of α-synuclein and tau linked to familial Parkinson's disease and frontotemporal dementia, respectively, reduced neurite outgrowth in cells deficient in ZIP12. Zinc and ZIP12 may confer resilience against neurological diseases or premature aging of the brain.

Astaxanthin-Shifted Gut Microbiota Is Associated with Inflammation and Metabolic Homeostasis in Mice.

BACKGROUND: Astaxanthin is a red lipophilic carotenoid that is often undetectable in human plasma due to the limited supply in typical Western diets. Despite its presence at lower than detectable concentrations, previous clinical feeding studies have reported that astaxanthin exhibits potent antioxidant properties. OBJECTIVE: We examined astaxanthin accumulation and its effects on gut microbiota, inflammation, and whole-body metabolic homeostasis in wild-type C57BL/6 J (WT) and ß-carotene oxygenase 2 (BCO2) knockout (KO) mice. METHODS: Six-wk-old male and female BCO2 KO and WT mice were provided with either nonpurified AIN93M (e.g., control diet) or the control diet supplemented with 0.04% astaxanthin (wt/wt) ad libitum for 8 wk. Whole-body energy expenditure was measured by indirect calorimetry. Feces were collected from individual mice for short-chain fatty acid assessment. Hepatic astaxanthin concentrations and liver metabolic markers, cecal gut microbiota profiling, inflammation markers in colonic lamina propria, and plasma samples were assessed. Data were analyzed by 3-way ANOVA followed by Tukey's post hoc analysis. RESULTS: BCO2 KO but not WT mice fed astaxanthin had ∼10-fold more of this compound in liver than controls (P < 0.05). In terms of the microbiota composition, deletion of BCO2 was associated with a significantly increased abundance of Mucispirillum schaedleri in mice regardless of gender. In addition to more liver astaxanthin in male KO compared with WT mice fed astaxanthin, the abundance of gut Akkermansia muciniphila was 385% greater, plasma glucagon-like peptide 1 was 27% greater, plasma glucagon and IL-1ß were 53% and 30% lower, respectively, and colon NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation was 23% lower (all P < 0.05) in male KO mice than the WT mice. CONCLUSIONS: Astaxanthin affects the gut microbiota composition in both genders, but the association with reductions in local and systemic inflammation, oxidative stress, and improvement of metabolic homeostasis only occurs in male mice.

Wheat Germ Supplementation Increases Lactobacillaceae and Promotes an Anti-inflammatory Gut Milieu in C57BL/6 Mice Fed a High-Fat, High-Sucrose Diet.

BACKGROUND: A link between high-fat diet consumption and obesity-related diseases is the disruption of the gut bacterial population, which promotes local and systemic inflammation. Wheat germ (WG) is rich in bioactive components with antioxidant and anti-inflammatory properties. OBJECTIVE: The aim of this study was to investigate the effects of WG supplementation in modulating the gut bacterial population and local and systemic inflammatory markers of mice fed a high-fat, high-sucrose (HFS) diet. METHODS: Six-week-old male C57BL/6 mice were randomly assigned to 4 groups (n = 12/group) and fed a control (C; 10% kcal fat, 10% kcal sucrose) or HFS (60% kcal fat, 20% kcal sucrose) diet with or without 10% WG (wt:wt) for 12 wk. Cecal bacteria was assessed via 16S rDNA sequencing, fecal short-chain fatty acids by GC, small intestinal CD4+ lymphocytes using flow cytometry, and gut antimicrobial peptide genes and inflammatory markers by quantitative polymerase chain reaction. Statistical analyses included Kruskal-Wallis/Dunn's test and 2-factor ANOVA using HFS and WG as factors. RESULTS: There was a 4-fold increase (P = 0.007) in the beneficial bacterial family, Lactobacillaceae, in the HFS + WG compared with the HFS group. Fecal propionic and n-butyric acids were elevated at least 2-fold in C + WG compared with the other groups (P < 0.0001). WG tended to increase (≥7%; P-trend = 0.12) small intestinal regulatory T cell:Th17 ratio, indicating a potential to induce an anti-inflammatory gut environment. WG elevated (≥35%) ileal gene expression of the anti-inflammatory cytokine Il10 compared to the unsupplemented groups (P = 0.038). Ileal gene expression of the antimicrobial peptides Reg3b and Reg3g was upregulated (≥95%) in the HFS + WG compared with other groups (P ≤ 0.040). WG reduced serum concentrations of the pro-inflammatory cytokines, interleukin (IL)-1B, IL-6, interferon-γ, and tumor necrosis factor-α (≥17%; P ≤ 0.012). CONCLUSIONS: WG selectively increased gut Lactobacillaceae, upregulated ileal antimicrobial peptides, and attenuated circulating pro-inflammatory cytokines of C57BL/6 mice fed a HFS diet. These changes may be vital in preventing HFS diet-induced comorbidities.

Effect of Long-Term Green Tea Polyphenol Supplementation on Bone Architecture, Turnover, and Mechanical Properties in Middle-Aged Ovariectomized Rats.

We investigated the effects of 6-month green tea polyphenols (GTP) supplementation on bone architecture, turnover, and mechanical properties in middle-aged ovariectomized (OVX) rats. Female rats were sham-operated (n = 39, 13/group) or OVX (n = 143, 13/group). Sham-control and OVX-control rats (n = 39) receiving no GTP were assigned for sample collection at baseline, 3, or 6 months. The remaining OVX rats (n = 104) were randomized to 0.15%, 0.5%, 1%, and 1.5% (g/dL) GTP for 3 or 6 months. Blood and bone samples were collected. Relative to the OVX-control group, GTP (1% and 1.5%) lowered serum procollagen type 1 N-terminal propeptide at 3 and 6 months, C-terminal telopeptides of type I collagen at 3 months, and insulin-like growth factor-I at 6 months. GTP did not affect bone mineral content and density. At 6 months, no dose of GTP positively affected trabecular bone volume based on microCT, but a higher cortical thickness and improved biomechanical properties of the femur mid-diaphysis was observed in the 1.5% GTP-treated group. At 3 and 6 months, GTP (0.5%, 1%, and 1.5%) had lower rates of trabecular bone formation and resorption than the OVX-control group, but the inhibitory effects of GTP on periosteal and endocortical bone mineralization and formation at the tibial midshaft were only evident at 3 months. GTP at higher doses suppressed bone turnover in the trabecular and cortical bone of OVX rats and resulted in improved cortical bone structural and biomechanical properties, although it was not effective in preventing the ovariectomy-induced dramatic cancellous bone loss.

Montmorency tart cherry protects against age-related bone loss in female C57BL/6 mice and demonstrates some anabolic effects.

PURPOSE: Age-related bone loss is a consequence of endocrine and immune changes that disrupt bone remodeling. Functional foods (e.g., tart cherries) with antioxidant, anti-inflammatory and prebiotic activity can potentially counter this age-related phenomenon. The aim of this study was to determine if Montmorency tart cherry protects against early age-related bone loss and the culpable alterations in bone metabolism. METHODS: Female, 5-month-old, C57BL/6 mice were assigned to baseline or treatment groups: AIN-93M diet supplemented with 0, 1, 5, or 10% tart cherry for 90 days. Bone mineral density (BMD) and trabecular and cortical bone microarchitecture were assessed. Treatment effects on bone metabolism and regulators of bone formation, resorption and mineralization were determined. RESULTS: Mice consuming the 5% and 10% doses had higher vertebral and tibial BMD (p < 0.05) compared to controls. The age-related decrease in trabecular bone volume (BV/TV) of the distal femur was prevented with these doses. Vertebral trabecular BV/TV and cortical bone thickness of the femur mid-diaphysis were greater (p < 0.05) in the groups receiving the 5% and 10% cherry than the control diet. Notably, these improvements were significantly greater than the baseline controls, consistent with an anabolic response. Although no differences in systemic biomarkers of bone formation or resorption were detected at 90 days, local increases in Phex and decreases in Ppar-γ suggest a bone environment that supports increased mineralization. CONCLUSIONS: These findings demonstrate that cherry supplementation (5% and 10%) improves BMD and some indices of trabecular and cortical bone microarchitecture; these effects are likely attributed to increased bone mineralization.

Wheat germ supplementation alleviates insulin resistance and cardiac mitochondrial dysfunction in an animal model of diet-induced obesity.

Obesity is strongly associated with insulin resistance (IR), along with mitochondrial dysfunction to metabolically active tissues and increased production of reactive O2 species (ROS). Foods rich in antioxidants such as wheat germ (WG), protect tissues from damage due to ROS and modulate some negative effects of obesity. This study examined the effects of WG supplementation on markers of IR, mitochondrial substrate metabolism and innate antioxidant markers in two metabolically active tissues (i.e. liver and heart) of C57BL/6 mice fed a high-fat-high-sucrose (HFS) diet. Male C57BL/6 mice, 6-week-old, were randomised into four dietary treatment groups (n 12 mice/group): control (C, 10 % fat kcal), C+10 % WG, HFS (60 % fat kcal) or HFS+10 % WG (HFS+WG). After 12 weeks of treatment, HFS+WG mice had significantly less visceral fat (-16 %, P=0·006) compared with the HFS group. WG significantly reduced serum insulin (P=0·009), the insulinotropic hormone, gastric inhibitory peptide (P=0·0003), and the surrogate measure of IR, homoeostatic model assessment of IR (P=0·006). HFS diet significantly elevated (45 %, P=0·02) cardiac complex 2 mitochondrial VO2, suggesting increased metabolic stress, whereas WG stabilised this effect to the level of control. Consequently, genes which mediate antioxidant defense and mitochondrial biogenesis (superoxide dismutase 2 (Sod2) and PPARγ coactivator 1-α (Pgc1a), respectively) were significantly reduced (P<0·05) in the heart of the HFS group, whereas WG supplementation tended to up-regulate both genes. WG significantly increased hepatic gene expression of Sod2 (P=0·048) but not Pgc1a. Together, these results showed that WG supplementation in HFS diet, reduced IR and improved cardiac mitochondrial metabolic functions.

Mango Supplementation Modulates Gut Microbial Dysbiosis and Short-Chain Fatty Acid Production Independent of Body Weight Reduction in C57BL/6 Mice Fed a High-Fat Diet.

BACKGROUND: High-fat (HF) diet-induced obesity is associated with changes in the gut microbiota. Fiber and other bioactive compounds in plant-based foods are suggested to prevent gut dysbiosis brought on by HF feeding. Mango is high in fiber and has been reported to have anti-obesogenic, hypoglycemic, and immunomodulatory properties. OBJECTIVES: We investigated the effects of freeze-dried mango pulp combined with an HF diet on the cecal microbial population and its relation to body composition, lipids, glucose parameters, short-chain fatty acid (SCFA) production, and gut inflammatory markers in a mouse model of diet-induced obesity. METHODS: Six-wk-old male C57BL/6 mice were randomly assigned to 1 of 4 dietary treatment groups: control (AIN-93M, 10% fat kcal), HF (60% fat kcal), and HF + 1% or 10% mango (HF+1%M or HF+10%M, wt:wt) for 12 wk. The cecal microbial population was assessed by use of 16S rDNA sequencing. Body composition, plasma glucose and lipids, cecal and fecal SCFAs, and mRNA abundance of inflammatory markers in the ileum and colonic lamina propria were assessed. RESULTS: Compared with the control group, HF feeding significantly reduced (P < 0.05) 1 operational taxonomic unit (OTU) of the genus Bifidobacteria (64-fold) and 5 OTUs of the genus Akkermansia (≥16-fold). This reduction was prevented in the HF+10%M group, members of which had 10% higher final body weight compared with the HF group (P = 0.01) and similar fasting blood glucose concentrations (P = 0.24). The HF+10%M group had 135% (P = 0.004) and 133% (P < 0.0001) greater fecal acetic and n-butyric acids concentrations than the HF group, suggesting greater microbial fermentation. Furthermore, a 59% greater colonic interleukin 10 (Il10) gene expression was observed in the HF+10%M group than in the HF group (P = 0.048), indicating modulation of gut inflammation. The HF+1%M group generally did not differ from the HF group. CONCLUSIONS: The addition of mango to an HF diet modulated the gut microbiota and production of SCFAs in C57BL/6 mice; these changes may improve gut tolerance to the insult of an HF diet.

Strain differences in the attenuation of bone accrual in a young growing mouse model of insulin resistance.

Skeletal fractures are considered a chronic complication of type 2 diabetes mellitus (T2DM), but the etiology of compromised bone quality that develops over time remains uncertain. This study investigated the concurrent alterations in metabolic and skeletal changes in two mouse strains, a responsive (C57BL/6) and a relatively resistant (C3H/HeJ) strain, to high-fat diet-induced glucose intolerance. Four-week-old male C57BL/6 and C3H/HeJ mice were randomized to a control (Con = 10 % kcal fat) or high-fat (HF = 60 % kcal fat) diet for 2, 8, or 16 weeks. Metabolic changes, including blood glucose, plasma insulin and leptin, and glucose tolerance were monitored over time in conjunction with alterations in bone structure and turn over. Elevated fasting glucose occurred in both the C57BL/6 and C3H/HeJ strains on the HF diet at 2 and 8 weeks, but only in the C57BL/6 strain at 16 weeks. Both strains on the HF diet demonstrated impaired glucose tolerance at each time point. The C57BL/6 mice on the HF diet exhibited lower whole-body bone mineral density (BMD) by 8 and 16 weeks, but the C3H/HeJ strain had no evidence of bone loss until 16 weeks. Analyses of bone microarchitecture revealed that trabecular bone accrual in the distal femur metaphysis was attenuated in the C57BL/6 mice on the HF diet at 8 and 16 weeks. In contrast, the C3H/HeJ mice were protected from the deleterious effects of the HF diet on trabecular bone. Alterations in gene expression from the femur revealed that several toll-like receptor (TLR)-4 targets (Atf4, Socs3, and Tlr4) were regulated by the HF diet in the C57BL/6 strain, but not in the C3H/HeJ strain. Structural changes observed only in the C57BL/6 mice were accompanied with a decrease in osteoblastogenesis after 8 and 16 weeks on the HF diet, suggesting a TLR-4-mediated mechanism in the suppression of bone formation. Both the C57BL/6 and C3H/HeJ mice demonstrated an increase in osteoclastogenesis after 8 weeks on the HF diet; however, bone turnover was decreased in the C57BL/6 with prolonged hyperglycemia. Further investigation is needed to understand how hyperglycemia and hyperinsulinemia suppress bone turnover in the context of T2DM and the role of TLR-4 in this response.

Compromised Vitamin D Status Negatively Affects Muscular Strength and Power of Collegiate Athletes.

Increasing evidence indicates that compromised vitamin D status, as indicated by serum 25-hydroxyvitamin D (25-OH D), is associated with decreased muscle function. The purpose of this study was to determine the vitamin D status of collegiate athletes residing in the southern U.S. and its effects on muscular strength and anaerobic power. Collegiate athletes (n = 103) from three separate NCAA athletic programs were recruited for the study. Anthropometrics, vitamin D and calcium intake, and sun exposure data were collected along with serum 25-OH D and physical performance measures (Vertical Jump Test, Shuttle Run Test, Triple Hop for Distance Test and the 1 Repetition Maximum Squat Test) to determine the influence of vitamin D status on muscular strength and anaerobic power. Approximately 68% of the study participants were vitamin D adequate (>75 nmol/L), whereas 23% were insufficient (75-50 nmol/L) and 9%, predominantly non-Caucasian athletes, were deficient (<50 nmol/L). Athletes who had lower vitamin D status had reduced performance scores (p < .01) with odds ratios of 0.85 on the Vertical Jump Test, 0.82 on the Shuttle Run Test, 0.28 on the Triple Hop for Distance Test, and 0.23 on the 1 RM Squat Test. These findings demonstrate that even NCAA athletes living in the southern US are at risk for vitamin D insufficiency and deficiency and that maintaining adequate vitamin D status may be important for these athletes to optimize their muscular strength and power.

Feeding soy protein isolate and oils rich in omega-3 polyunsaturated fatty acids affected mineral balance, but not bone in a rat model of autosomal recessive polycystic kidney disease.

BACKGROUND: Polycystic kidney disease (PKD), a genetic disorder characterized by multiple cysts and renal failure at an early age. In children, kidney disease is often accompanied by disordered mineral metabolism, failure to achieve peak bone mass, and reduced adult height. Optimizing bone health during the growth stage may preserve against bone loss associated with early renal dysfunction in PKD. Dietary soy protein and omega-3 polyunsaturated fatty acid (n-3 PUFA) have been reported to ameliorate PKD and to promote bone health. The study objective was to determine the bone effects of feeding soy protein and/or n-3 PUFAs in a rat model of PKD. METHODS: Weanling female PCK rats (n = 12/group) were randomly assigned to casein + corn oil (Casein + CO), casein + soybean oil (Casein + SO), soy protein isolate + soybean oil (SPI + SO) or soy protein isolate + 1:1 soybean oil:salmon oil blend (SPI + SB) for 12 weeks. RESULTS: Rats fed SPI + SO diet had shorter (P = 0.001) femur length than casein-fed rats. Rats fed SPI + SO and SPI + SB diet had higher (P = 0.04) calcium (Ca) and phosphorus (P) retention. However, there were no significant differences in femur and tibial Ca, P or bone mass between diet groups. There were also no significant difference in bone microarchitecture measured by micro-computed tomography or bone strength determined by three-point bending test between diet groups. CONCLUSIONS: Early diet management of PKD using SPI and/or n-3 PUFAs influenced bone longitudinal growth and mineral balance, but neither worsened nor enhanced bone mineralization, microarchitecture or strength.

Intermolecular interactions in solid-state metalloporphyrins and their impacts on crystal and molecular structures.

A variable-temperature (VT) crystal structure study of [Fe(TPP)Cl] (TPP(2-) = meso-tetraphenylporphyrinate) and Hirshfeld surface analyses of its structures and previously reported structures of [M(TPP)(NO)] (M = Fe, Co) reveal that intermolecular interactions are a significant factor in structure disorder in the three metalloporphyrins and phase changes in the nitrosyl complexes. These interactions cause, for example, an 8-fold disorder in the crystal structures of [M(TPP)(NO)] at room temperature that obscures the M-NO binding. Hirshfeld analyses of the structure of [Co(TPP)(NO)] indicate that the phase change from I4/m to P1 leads to an increase in void-volume percentage, permitting additional structural compression through tilting of the phenyl rings to offset the close-packing interactions at the interlayer positions in the crystal structures with temperature decrease. X-ray and neutron structure studies of [Fe(TPP)Cl] at 293, 143, and 20 K reveal a tilting of the phenyl groups away from being perpendicular to the porphyrin ring as a result of intermolecular interactions. Structural similarities and differences among the three complexes are identified and described by Hirshfeld surface and void-volume calculations.

Exerkines, Nutrition, and Systemic Metabolism.

The cornerstones of good health are exercise, proper food, and sound nutrition. Physical exercise should be a lifelong routine, supported by proper food selections to satisfy nutrient requirements based on energy needs, energy management, and variety to achieve optimal metabolism and physiology. The human body is sustained by intermediary and systemic metabolism integrating the physiologic processes for cells, tissues, organs, and systems. Recently, interest in specific metabolites, growth factors, cytokines, and hormones called exerkines has emerged to explain cooperation between nutrient supply organs and the brain during exercise. Exerkines consist of different compounds described as signaling moiety released during and after exercise. Examples of exerkines include oxylipin 12, 13 diHOME, lipid hormone adiponectin, growth factor BDNF, metabolite lactate, reactive oxygen species (ROS), including products of fatty acid oxidation, and cytokines such as interleukin-6. At this point, it is believed that exerkines are immediate, fast, and long-lasting factors resulting from exercise to support body energy needs with an emphasis on the brain. Although exerkines that are directly a product of macronutrient metabolism such as lactate, and result from catabolism is not surprising. Furthermore, other metabolites of macronutrient metabolism seem to be candidate exerkines. The exerkines originate from muscle, adipose, and liver and support brain metabolism, energy, and physiology. The purpose of this review is to integrate the actions of exerkines with respect to metabolism that occurs during exercise and propose other participating factors of exercise and brain physiology. The role of diet and macronutrients that influence metabolism and, consequently, the impact of exercise will be discussed. This review will also describe the evidence for PUFA, their metabolic and physiologic derivatives endocannabinoids, and oxylipins that validate them being exerkines. The intent is to present additional insights to better understand exerkines with respect to systemic metabolism.

Older adults' online activities and cognition: Investigating the psychological mechanisms and age and gender differences.

OBJECTIVES: This study aimed to investigate psychological mechanisms underlying the association between older adults' Internet use and cognition and examine potential age and gender group differences. METHODS: 2064 older participants were extracted from the Waves 2012, 2013, and 2016 Health and Retirement Study. Internet use was measured by two sets of variables: Internet access and different types of online activities (i.e., informational use, social use, online shopping, and online banking). Path analyses were applied to test the proposed mechanisms via three mediators (i.e., loneliness, depressive symptoms, and perceived control). Multi-group analyses were conducted to examine the potential group differences. RESULTS: Internet use was positively associated with cognition. Despite the large direct effect, small but significant indirect effects via depressive symptoms and perceived control were identified across all online activities. Multi-group analyses revealed age-group differences in the mechanisms: depressive symptoms mediated the effects of all online activities on cognition among young-old adults, while perceived control mediated all the effects among old-old adults. Gender group differences were also identified: depressive symptoms mediated the effects of all online activities on cognition among older women and most online activities among older men, whereas perceived control mediated the associations between informational and instrumental (i.e., online shopping and banking) use and cognition among older men. DISCUSSION: This study highlights the mediating effect of depressive symptoms and perceived control and age and gender differences regarding the Internet use-cognition association. Internet-based cognitive interventions should consider these psychological mediators and age and gender differences for the best results.

Examining First- and Second-Level Digital Divide at the Intersection of Race/Ethnicity, Gender, and Socioeconomic Status: An Analysis of the National Health and Aging Trends Study.

BACKGROUND AND OBJECTIVES: Significant societal and technological changes in the 2010s called for an up-to-date understanding of the digital divide among older adults in the United States. This trend study aimed to examine the effects of race/ethnicity and the intersecting effects of race/ethnicity with other marginalized identities related to gender, income, education, and occupation on the first- and second-level digital divide. RESEARCH DESIGN AND METHODS: Utilizing a nationally representative sample of older community dwellers from the National Health and Aging Trends Study, we conducted weighted logistic regressions at 3 time points (2011/2013, 2015, and 2019). The first-level digital divide was measured by access to working phones or computers/laptops; the second-level divide was measured by 7 activities in personal task, social, and health-related Internet use. RESULTS: The first-level racial/ethnic digital divide became nonsignificant in 2019, whereas the disparities in all second-level measures persisted. The intersecting effects of race/ethnicity with low education and/or low income became nonsignificant in 2019 for personal-task use. However, the interactions with low education and/or low income became significant for social and health-related use in 2015 and/or 2019. DISCUSSION AND IMPLICATIONS: This study highlights the persistence of the second-level racial/ethnic digital divide among older community dwellers in the United States, especially the exacerbated social and health-related digital divide for people of color with low socioeconomic status. By considering intersections of marginalized social identities, policymakers and stakeholders should develop targeted strategies to bridge the digital divide, promote health outcomes, and reduce health disparities.

Reduced estrogen signaling contributes to bone loss and cardiac dysfunction in interleukin-10 knockout mice.

Characterization of the interleukin (IL)-10 knockout (KO) mouse with chronic gut inflammation, cardiovascular dysfunction, and bone loss suggests a critical role for this cytokine in interorgan communication within the gut, bone, and cardiovascular axis. We sought to understand the role of IL-10 in the cross-talk between these systems. Six-week-old IL-10 KO mice and their wild type (WT) counterparts were maintained on a standard rodent diet for 3 or 6 months. Gene expression of proinflammatory markers and Fgf23, serum 17ß-estradiol (E2), and cardiac protein expression were assessed. Ileal Il17a and Tnf mRNA increased while Il6 mRNA increased in the bone and heart by at least 2-fold in IL-10 KO mice. Bone Dmp1 and Phex mRNA were repressed at 6 months in IL-10 KO mice, resulting in increased Fgf23 mRNA (~4-fold) that contributed to increased fibrosis. In the IL-10 KO mice, gut bacterial ß-glucuronidase activity and ovarian Cyp19a1 mRNA were lower (p < 0.05), consistent with reduced serum E2 and reduced cardiac pNOS3 (Ser1119 ) in these mice. Treatment of ileal lymphocytes with E2 reduced gut inflammation in WT but not IL-10 KO mice. In conclusion, our data suggest that diminished estrogen and defective bone mineralization increased FGF23 which contributed to cardiac fibrosis in the IL-10 KO mouse.

Wheat germ supplementation has modest effects on gut health markers but improves glucose homeostasis markers in adults classified as overweight: A randomized controlled pilot study.

Wheat germ (WG), a by-product of flour milling, is rich in bioactive substances that may help improve health complications associated with increased adiposity. This study investigated the effects of WG on gut health, metabolic, and inflammatory markers in adults classified as overweight. We hypothesized that WG, because of its many bioactive components, would improve gut health and metabolic, and inflammatory markers in overweight adults. Forty adults (18-45 years old) and with a body mass index between 25 and 30 kg/m2 participated in this single-blinded randomized controlled pilot study. Participants consumed the study supplements containing 30 g of either cornmeal (control, CL) or WG daily for 4 weeks. Primary outcome variables were gut health markers including gut microbiota, gut integrity markers, and fecal short-chain fatty acids, whereas secondary outcome variables included metabolic and inflammatory parameters assessed at baseline and at the end of supplementation. Thirty-nine participants (n = 19 and 20 for CL and WG group, respectively) completed the study. The genus Faecalibacterium was significantly higher in the WG group compared to CL post-supplementation but no significant changes in other gut health markers, short-chain fatty acids, inflammatory markers, and lipid profiles were observed. Compared with baseline, WG improved markers of glucose homeostasis including insulin (P = .02), homeostatic model assessment of insulin resistance (P = .03), glycated hemoglobin (P = .07), and the pro-inflammatory adipokine, resistin (P = .04). However, these parameters after intervention were not different with control. Our findings suggest that WG supplementation have modest effects on gut health but may provide an economical option for individuals to improve glycemic control.

Rodent and broiler feeding studies with maize containing genetically modified event DP-915635-4 show no adverse effects on health or performance.

Several regulatory agencies continue to require animal feeding studies to approve new genetically modified crops despite such studies providing little value in the safety assessment. Feeding studies with maize grain containing event DP-915635-4 (DP915635), a new corn rootworm management trait, were conducted to fulfill that requirement. Diets fed to Crl:CD®(SD) rats for 90 days contained up to 50% ground maize grain from DP915635, non-transgenic control, or non-transgenic reference hybrids (P1197, 6158, and 6365). Ross 708 broilers received phase diets containing up to 67% maize grain from each source for 42 days. Growth performance was compared between animals fed DP915635 and control diets; rats were further evaluated for clinical and neurobehavioral measures, ophthalmology, clinical pathology, organ weights, and gross and microscopic pathology, whereas carcass parts and select organ yields were determined for broilers. Reference group inclusion assisted in determining natural variation influence on observed significant differences between DP915635 and control groups. DP915635 maize grain diet consumption did not affect any measure evaluated in either feeding study. Results demonstrated DP-915635-4 maize grain safety and nutritional equivalency when fed in nutritionally adequate diets, adding to the existing literature confirming the lack of significant effects of feeding grain from genetically modified plants.