Lachnospiraceae-derived butyrate mediates protection of high fermentable fiber against placental inflammation in gestational diabetes mellitus.

Inflammation-associated insulin resistance is a key trigger of gestational diabetes mellitus (GDM), but the underlying mechanisms and effective interventions remain unclear. Here, we report the association of placental inflammation (tumor necrosis factor-α) and abnormal maternal glucose metabolism in patients with GDM, and a high fermentable dietary fiber (HFDF; konjac) could reduce GDM development through gut flora-short-chain fatty acid-placental inflammation axis in GDM mouse model. Mechanistically, HFDF increases abundances of Lachnospiraceae and butyrate, reduces placental-derived inflammation by enhancing gut barrier and inhibiting the transfer of bacterial-derived lipopolysaccharide, and ultimately resists high-fat diet-induced insulin resistance. Lachnospiraceae and butyrate have similar anti-GDM and anti-placental inflammation effects, and they can ameliorate placental function and pregnancy outcome effects probably by dampening placental immune dysfunction. These findings demonstrate the involvement of important placental inflammation-related mechanisms in the progression of GDM and the great potential of HFDFs to reduce susceptibility to GDM through gut-flora-placenta axis.

Dietary adenosine supplementation improves placental angiogenesis in IUGR piglets by up-regulating adenosine A2a receptor.

Abnormal placental angiogenesis is associated with the occurrence of intrauterine growth restriction (IUGR) in piglets, and effective treatment strategies against this occurrence remain to be explored. Adenosine has been reported to play an important role in angiogenesis, but its role in placental angiogenesis is still unknown. Here, we investigated the effect of dietary adenosine supplementation on IUGR occurrence in piglets by analyzing the role of adenosine in placental angiogenesis for Normal and IUGR piglets. Specifically, 88 sows were allotted to 2 treatments (n = 44) and fed a basal diet supplemented with 0% or 0.1% of adenosine from day 65 of gestation until farrowing, followed by collecting the placental samples of Normal and IUGR piglets, and recording their characteristics. The results showed that adenosine supplementation increased the mean birth weight of piglets (P < 0.05) and placental efficiency (P < 0.05), while decreasing the IUGR piglet rate (P < 0.05). Expectedly, the placenta for IUGR neonates showed a down-regulated vascular density (P < 0.05) and angiogenesis as evidenced by the expression level of vascular cell adhesion molecule-1 (VCAM1) (P < 0.05). Notably, dietary adenosine supplementation promoted angiogenesis (P < 0.05) both in the Normal and IUGR placenta. More importantly, the expression level of adenosine A2a receptor (ADORA2A) was lower (P < 0.05) in the IUGR placenta than in Normal placenta, whereas adenosine treatment could significantly increase ADORA2A expression, and also had an interaction effect between factors IUGR and Ado. Collectively, placentae for IUGR piglets showed impaired angiogenesis and down-regulated expression level of ADORA2A, while dietary adenosine supplementation could activate ADORA2A expression, improve the placental angiogenesis, and ultimately decrease the occurrence of IUGR in piglets.

Dietary fibers with low hydration properties exacerbate diarrhea and impair intestinal health and nutrient digestibility in weaned piglets.

BACKGROUND: This study aimed to investigate the hydration properties of different-source fibrous materials by comparing their water-binding capacity (WBC), water swelling capacity (WSC), viscosity, and in vivo effects of selected samples on growth performance, nutrient digestibility, diarrhea, and intestinal health in weaned piglets. METHODS: A total of 13 commercially available fibrous materials were first compared in chemical composition and in vitro hydration property. Subsequently, 40 weaned piglets were randomized to five experimental dietary groups (8 piglets per group): control diet (a basal diet without dietary fiber, CON), basal diet supplemented with 5% microcrystalline cellulose (MCC), 5% wheat bran (WB), 5% Moringa oleifera leaf powder (MOLP), or 5% sugar beet pulp (SBP), followed by analyzing their growth performance and diarrhea rate in a 28-d experiment. After the feeding experiment, anaesthetized piglets were killed, and their intestinal and colon content or plasma samples were analyzed in nutrient digestibility, intestinal morphology, intestinal barrier, short-chain fatty acids (SCFAs), and bacterial population. RESULTS: In vitro studies showed low hydration properties for WB and MCC, while medium hydration properties for MOLP and SBP. In vivo studies indicated that compared with medium hydration property groups, low hydration property groups showed (1) exacerbated diarrhea, impaired intestinal health, and reduced apparent fecal digestibility of dry matter, gross energy, acid detergent fiber, and neutral detergent fiber; (2) decreased SCFAs concentration and relative levels of Lactobacillus and Bifidobacterium, but increased levels of Escherichia coli and Brachyspira hyodysenteriae in colon contents. Additionally, SBP showed optimal performance in reducing diarrhea and increasing SCFAs production. Correlation analysis revealed a positive correlation of fiber hydration properties with in vitro SCFAs production, and diarrhea index and nutrient digestibility were negatively and positively correlated with SCFAs levels in the colon contents of weaned piglets, respectively. CONCLUSIONS: Different-source dietary fibers varied in their hydration properties and impacts on diarrhea, microbial composition and SCFAs production in weaned piglets. WB and MCC could exacerbate diarrhea and impair nutrient digestibility, probably because their low hydration properties were detrimental to gut microbial homeostasis and fermentation. Our findings provide new ideas for rational use of fiber resources in weaned piglets.

Dietary adenosine 5'-monophosphate supplementation increases food intake and remodels energy expenditure in mice.

Background: Dietary nucleotides [inclusion adenosine 5'-monophosphate (AMP)] supplementation was shown to promote the feed intake of sows and increase the AMP content in their milk in our previous work, but whether AMP shapes the energy expenditure and lipid metabolism in mammals remains unknown. Here, we aimed to explore the effects and the related mechanism of dietary AMP supplementation on food intake, body composition, energy expenditure, and lipid metabolism in male mice. Methods: 4-week-old C57BL/6 mice (After a 1-wk adaptation) were fed with basal diet and basal diet supplemented with 0.1% AMP, respectively. Animal food intake and body weight were monitored and after 4 weeks all animals were sacrificed to measure the body composition, energy expenditure and lipid metabolism changes. Results: Compared with the control, the 0.1% AMP fed mice showed higher food intake while lower adipose weight. Intriguingly, dietary AMP supplementation was found to stimulate brown adipose tissue thermogenesis as evidenced by the increase in the uncoupling protein-1 level and the core temperature. Moreover, AMP supplementation was shown to promote white adipose tissue lipolysis as indicated by smaller lipid droplet size in mice. These results demonstrate that dietary AMP supplementation could enhance oxygen consumption and energy expenditure. Conclusions: This study highlights the physiological importance of AMP supplementation in mediating food intake and energy expenditure and suggests its potential as an adjuvant therapy in preventing energy metabolic disorders (mainly obesity and diabetes).

Starch supplementation improves the reproductive performance of sows in different glucose tolerance status.

This study was to evaluate the effects of glucose tolerance status, maternal starch supplementation and soybean substitution in diets on the performance of dams and their offspring. Eighty-eight pregnant sows (Landrace × Large White) were selected from an initial total of 120 sows, based on blood glucose test values, and assigned to 4 experimental treatments in a 2 × 2 factorial design. The factors were glucose tolerance status (glucose intolerant [GIT] vs. normal glucose tolerant [NGT]) or dietary treatments (corn starch diet [CS] vs. soybean substitution diet [SS]). A higher area under the curve (AUC) for post-meal glucose was observed (P < 0.05) in the GIT group than in the NGT group on d 109 of gestation. The CS group had a lower value of homeostasis model assessment-insulin resistance than the SS group (P < 0.05) on d 109 of gestation. Corn starch supplementation for sows decreased the stillbirth rate (P < 0.05), regardless of the sows' glucose tolerance status. The villus height of the jejunum and the villus height to crypt depth ratio of the ileum were greater in normal birth weight piglets from the CS group than from the SS group (P < 0.01), and so was the activity of sucrase in the jejunum and ileum (P < 0.01). Compared with the SS group, the CS group showed a reduction in pre-weaning mortality rate, an increase in the number of high-birth-weight piglets, and a decrease in the number of low-birth-weight piglets (P < 0.05) under GIT status. In conclusion, sows fed CS decreased stillbirth rate and improved insulin resistance, as well as improving the intestinal morphology and digestive enzyme activities of their progeny, regardless of glucose tolerance status. Additionally, the CS group improved birth weight distribution and decreased pre-weaning mortality rate of piglets under GIT status.

Efficacy, Safety, and Tumor Marker Inhibition of Apatinib Combined with Conventional Chemotherapy Regimens for Patients with Advanced Triple-Negative Breast Cancer.

OBJECTIVE: Triple-negative breast cancer (TNBC) is an aggressive disease with highly invasive nature and poor outcomes. Due to the absence of specific treatment strategies for this tumor subgroup, patients with TNBC are treated with conventional therapeutics, frequently leading to systemic relapse. In this study, we sought to investigate apatinib combined with conventional chemotherapy regimens in treating patients with advanced TNBC concerning the efficacy, safety, expressions of tumor markers, and patient survival. METHODS: This is a prospective study including 150 cases of advanced TNBC who were randomly arranged into a conventional group and combined group, with 75 cases per group. The patients in the conventional group were treated with conventional chemotherapy, and those in the combined group were treated with apatinib combined with conventional chemotherapy. The peripheral blood was collected from each patient, and carcinoembryonic antigen (CEA), carbohydrate antigen 153 (CA153), and carbohydrate antigen 125 (CA125) were determined. The expressions of nuclear proliferation antigen marker (Ki67), ß-catenin, and E-cadherin were determined in the biopsy collected from each patient. RESULTS: The objective remission rate (ORR) and disease control rate (DCR) (41.33% and 81.33%) in the combined group were notably higher than those in the conventional group (29.33% and 68.00%) (P < 0.05). After treatment, the serum levels of CEA, CA153, and CA125 and the expressions of Ki67 and ß-catenin were declined, but the expression of E-cadherin was increased in both groups; the combined group exhibited lower serum levels of CEA, CA153, and CA125, and the expressions of Ki67 and ß-catenin were concurrent with a higher expression of E-cadherin than the conventional group (P < 0.05). No significant difference was noted between the two groups regarding the occurrence of adverse reactions (P > 0.05). Improved progression-free survival (PFS) was observed in the combined group compared to the conventional group (P < 0.05. CONCLUSION: These findings suggest that apatinib combined with conventional chemotherapy regimens confers a prolonged PFS for treating patients with advanced TNBC.

Inclusion of wheat aleurone in gestation diets improves postprandial satiety, stress status and stillbirth rate of sows.

This study investigated the effects of different amounts of wheat aleurone (WA) (0, 15%, 30%) inclusion in gestation diets on the reproductive performance, postprandial satiety, stress status and stereotypic behaviors of sows. A total of 84 Landrace × Yorkshire sows (parity 4.87 ± 1.32) at breeding were randomly allotted to one of the three isoenergetic and isonitrogenous dietary treatments based on parity and body weight. The results showed that, compared with the control (0), sows fed the WA diet had a higher serum concentration of peptide YY (PYY) (P < 0.05) and glucagon like peptide-1 (GLP-1) (P < 0.05) and a lower concentration of saliva cortisol (P < 0.01). Importantly, compared with the control group, only the 15% WA group had a higher concentration of the total antioxidant capacity (T-AOC) (P < 0.05), lower proportions of sitting (P = 0.05) and stillbirth rates (P < 0.01). Accordingly, the production cost per piglet born alive ($ 6.9 vs. $ 7.6) or per piglet born healthy ($ 7.4 vs. $ 7.9) declined in the 15% WA group versus the control group. Overall, 15% WA inclusion in gestation diets contributed to enhancing postprandial satiety, alleviating stress status and decreasing stillbirth rate of sows. This study provides a reference for the application of WA as a partial substitute for conventional feed ingredients to improve sows' reproductive performance.

Anti-Nociceptive and Anti-Inflammation Effect Mechanisms of Mutants of Syb-prII, a Recombinant Neurotoxic Polypeptide.

Syb-prII, a recombinant neurotoxic polypeptide, has analgesic effects with medicinal value. Previous experiments indicated that Syb-prII displayed strong analgesic activities. Therefore, a series of in vivo and vitro experiments were designed to investigate the analgesic and anti-inflammatory properties and possible mechanisms of Syb-prII. The results showed that administered Syb-prII-1 and Syb-prII-2 (0.5, 1, 2.0 mg/kg, i.v.) to mice significantly reduced the time of licking, biting, or flicking of paws in two phases in formalin-induced inflammatory nociception. Syb-prII-1 inhibited xylene-induced auricular swelling in a dose-dependent manner. The inhibitory effect of 2.0 mg/kg Syb-prII-1 on the ear swelling model was comparable to that of 200 mg/kg aspirin. In addition, the ELISA and Western blot analysis suggested that Syb-prII-1 and Syb-prII-2 may exert an analgesic effect by inhibiting the expression of Nav1.8 and the phosphorylation of ERK, JNK, and P38. Syb-prII-1 markedly suppressed the expression of IL-1ß, IL-6, and TNF-α of mice in formalin-induced inflammatory nociception. We used the patch-clamp technique and investigated the effect of Syb-prII-1 on TTX-resistant sodium channel currents in acutely isolated rat DRG neurons. The results showed that Syb-prII-1 can significantly down regulate TTX-resistant sodium channel currents. In conclusion, Syb-prII mutants may alleviate inflammatory pain by significantly inhibiting the expression of Nav1.8, mediated by the phosphorylation of MAPKs and significant inhibition of TTX-resistant sodium channel currents.

Antinociceptive Effects of AGAP, a Recombinant Neurotoxic Polypeptide: Possible Involvement of the Tetrodotoxin-Resistant Sodium Channels in Small Dorsal Root Ganglia Neurons.

Antitumor-analgesic peptide (AGAP) is a novel recombinant polypeptide. The primary study showed that AGAP 1.0 mg/kg exhibited strong analgesic and antitumor effects. The tail vein administration of AGAP potently reduced pain behaviors in mice induced by intraplantar injection of formalin or intraperitoneal injection of acetic acid, without affecting basal pain perception. To further assess the mechanisms of AGAP, the effects of AGAP on sodium channels were assessed using the whole-cell patch clamp recordings in dorsal root ganglia (DRG) neurons. The results showed that AGAP (3-1000 nM) inhibited the sodium currents in small-diameter DRG neurons in a dose-dependent manner. 1000 nM AGAP could inhibit the current density-voltage relationship curve of sodium channels in a voltage-dependent manner and negatively shift the activation curves. 1000 nM AGAP could reduce the tetrodotoxin-resistant (TTX-R) sodium currents by 42.8% in small-diameter DRG neurons. Further analysis revealed that AGAP potently inhibited NaV1.8 currents by 59.4%, and negatively shifted the activation and inactivation kinetics. 1000 nM AGAP also reduced the NaV1.9 currents by 33.7%, but had no significant effect on activation and inactivation kinetics. Thus, our results demonstrated that submicromolar concentrations of AGAP inhibited TTX-R sodium channel in rat small-diameter DRG neurons. It is concluded that these new results may better explain, at least in part, the analgesic properties of this polypeptide.

Positive shift of Nav1.8 current inactivation curve in injured neurons causes neuropathic pain following chronic constriction injury.

Neuropathic pain is a global medical concern, characterized by spontaneous pain, heat hyperalgesia and mechanical allodynia. The condition has been associated with alterations in the voltage­gated sodium channels, Nav1.8 and Nav1.9, in nociceptive neurons termed nociceptors. However, an explanation for the contribution of these channels to the phenotype observed in neuropathic pain remains to be elucidated. The changes induced by chronic constriction injury (CCI) to Nav1.8 and Nav1.9 mRNA and protein levels, as well as electrical currents in injured and contralateral non­injured dorsal root ganglion (DRG) neurons are described in the present study. A marked downregulation was observed for each Nav isoform transcript and protein expressed in injured neurons with the exception of the Nav1.9 protein, which exhibited no change, while in contralateral non­injured neurons, the levels of protein and mRNA remained unchanged. Nav isoform functional analysis was then performed in L(4­6) DRG neurons 14 days after CCI. The Nav1.8 current density was markedly decreased in injured DRG neurons following CCI. The voltage­dependent activation of the Nav1.8 channel in these neurons was shifted to depolarized potentials by 5.3 mV, while it was shifted to hyperpolarized potentials by 10 mV for inactivation. The electrophysiological function of Nav1.9 was not affected by CCI. The present study demonstrated that ectopic discharge following CCI, which was likely induced by a positive shift in the Nav1.8 current inactivation curve in injured neurons, enhanced the excitability of the neurons by facilitating tetrodotoxin­resistant sodium channels into the fast inactivation state and did not occur as a result of a compensatory redistribution in the contralateral uninjured neurons.

AGAP, a new recombinant neurotoxic polypeptide, targets the voltage-gated calcium channels in rat small diameter DRG neurons.

A previous study showed that antitumor-analgesic peptide (AGAP), a novel recombinant polypeptide, which had been expressed in Escherichia coli, exhibits analgesic and antitumor effects in mice. In the present study, we investigated the underlying analgesic mechanism of AGAP. The effect of AGAP on voltage-gated calcium channels (VGCCs) was assessed in acutely isolated rat dorsal root ganglia (DRG) neurons using the whole-cell patch clamp technique. The results showed that AGAP potently inhibited VGCCs, especially high-voltage activated (HVA) calcium channels. AGAP inhibited HVA and T-type calcium currents in a dose-dependent manner, but had no significant effect on their dynamic functions in rat small-diameter DRG neurons. AGAP inhibited N- and L-type calcium currents at 78.2% and 57.3%, respectively. Thus, the present study demonstrates that AGAP affects calcium currents through the inhibition of N-, L- and T-type channels in DRG neurons, explaining the potential mechanisms of antinociception.

Preparation and biomedical application of a non-polymer coated superparamagnetic nanoparticle.

We report the preparation of a non-polymer coated superparamagnetic nanoparticle that is stable and biocompatible both in vitro and in vivo. The non-polymer, betaine, is a natural methylating agent in mammalian liver with active surface property. Upon systemic administration, the nanoparticle has preferential biodistribution in mammalian liver and exhibits good reduction of relaxivity time and negative enhancement for the detection of hepatoma nodules in rats using MRI. Our data demonstrate that the non-polymer coated superparamagnetic nanoparticle should have potential applications in biomedicine.