A Novel Mechanism for T1R-Independent Taste Responses to Concentrated Sugars.

Recent findings from our laboratory demonstrated that the rostral nucleus of the solitary tract (rNST) retains some responsiveness to sugars in double-knock-out mice lacking either the T1R1+T1R3 (KO1+3) or T1R2+T1R3 (KO2+3) taste receptor heterodimers. Here, we extended these findings in the parabrachial nucleus (PBN) of male and female KO1+3 mice using warm stimuli to optimize sugar responses and employing additional concentrations and pharmacological agents to probe mechanisms. PBN T1R-independent sugar responses, including those to concentrated glucose, were more evident than in rNST. Similar to the NST, there were no "sugar-best" neurons in KO1+3 mice. Nevertheless, 1000 mm glucose activated nearly 55% of PBN neurons, with responses usually occurring in neurons that also displayed acid and amiloride-insensitive NaCl responses. In wild-type (WT) mice, concentrated sugars activated the same electrolyte-sensitive neurons but also "sugar-best" cells. Regardless of genotype, phlorizin, an inhibitor of the sodium-glucose co-transporter (SGLT), a component of a hypothesized alternate glucose-sensing mechanism, did not diminish responses to 1000 mm glucose. The efficacy of concentrated sugars for driving neurons broadly responsive to electrolytes implied an origin from Type III taste bud cells. To test this, we used the carbonic anhydrase (CA) inhibitor dorzolamide (DRZ), previously shown to inhibit amiloride-insensitive sodium responses arising from Type III taste bud cells. Dorzolamide had no effect on sugar-elicited responses in WT sugar-best PBN neurons but strongly suppressed them in WT and KO1+3 electrolyte-generalist neurons. These findings suggest a novel T1R-independent mechanism for hyperosmotic sugars, involving a CA-dependent mechanism in Type III taste bud cells.SIGNIFICANCE STATEMENT Since the discovery of Tas1r receptors for sugars and artificial sweeteners, evidence has accrued that mice lacking these receptors maintain some behavioral, physiological, and neural responsiveness to sugars. But the substrate(s) has remained elusive. Here, we recorded from parabrachial nucleus (PBN) taste neurons and identified T1R-independent responses to hyperosmotic sugars dependent on carbonic anhydrase (CA) and occurring primarily in neurons broadly responsive to NaCl and acid, implying an origin from Type III taste bud cells. The effectiveness of different sugars in driving these T1R-independent responses did not correlate with their efficacy in driving licking, suggesting they evoke a nonsweet sensation. Nevertheless, these salient responses are likely to comprise an adequate cue for learned preferences that occur in the absence of T1R receptors.

Auxin-independent effects of apical dominance induce changes in phytohormones correlated with bud outgrowth.

The inhibition of shoot branching by the growing shoot tip of plants, termed apical dominance, was originally thought to be mediated by auxin. Recently, the importance of the shoot tip sink strength during apical dominance has re-emerged with recent studies highlighting roles for sugars in promoting branching. This raises many unanswered questions on the relative roles of auxin and sugars in apical dominance. Here we show that auxin depletion after decapitation is not always the initial trigger of rapid cytokinin (CK) increases in buds that are instead correlated with enhanced sugars. Auxin may also act through strigolactones (SLs) which have been shown to suppress branching after decapitation, but here we show that SLs do not have a significant effect on initial bud outgrowth after decapitation. We report here that when sucrose or CK is abundant, SLs are less inhibitory during the bud release stage compared to during later stages and that SL treatment rapidly inhibits CK accumulation in pea (Pisum sativum) axillary buds of intact plants. After initial bud release, we find an important role of gibberellin (GA) in promoting sustained bud growth downstream of auxin. We are, therefore, able to suggest a model of apical dominance that integrates auxin, sucrose, SLs, CKs, and GAs and describes differences in signalling across stages of bud release to sustained growth.

Dietary administration of yeast (Saccharomyces cerevisiae) hydrolysate from sugar byproducts promotes the growth, survival, immunity, microbial community and disease resistance to VP (AHPND) in Pacific white shrimp (Litopenaeus vannamei).

This study investigated the effects of yeast hydrolysate (YH) from sugar byproducts on various parameters in Pacific white shrimp (Litopenaeus vannamei). The study found no significant differences in water quality parameters across all treatment tanks, ensuring that the observed effects were not due to environmental variations. There were no significant differences in growth parameters between the control group and groups receiving YH at different dosages. However, the group given YH at 10.0 g/kg feed exhibited a notably higher survival rate and higher expression of growth-related genes (IGF-2 and RAP-2A) in various shrimp tissues. YH was associated with enhanced immune responses, including lysozyme activity, NBT dye reduction, bactericidal activity, and phagocytic activity. Notably, the 10.0 g/kg feed group displayed the highest phagocytic index, indicating a dose-dependent immune response. Expression of immune-related genes (ALF, LYZ, ProPO, and SOD) was upregulated in various shrimp tissues. This upregulation was particularly significant in the gills, hepatopancreas, intestine, and hemocytes. While total Vibrio counts remained consistent, a reduction in green Vibrio colonies was observed in the intestine of shrimp treated with YH. YH, especially at 5.0 and 10.0 g/kg feed dosages, significantly increased survival rates and RPS values in response to AHPND infection. The findings of this study suggest that incorporating additives derived from yeast byproducts with possible prebiotic properties obtained from sugar byproducts can lead to positive results in terms of enhancing growth performance, immunity, histological improvements, and resistance to V. parahaemolyticus, the causative agent of acute hepatopancreatic necrosis disease (AHPND).

Fat and not sugar as the determining factor for gut microbiota changes, obesity, and related metabolic disorders in mice.

Diet-induced obesity contributes to the development of type 2 diabetes, insulin resistance, metabolic inflammation, oxidative and endoplasmic reticulum (ER) stress. Overall, obesity is associated with deviations in the composition and functionality of the gut microbiota. There are many divergent findings regarding the link between the excessive intake of certain dietary components (i.e., fat and sugar) and obesity development. We therefore investigated the effect of specific diets, with a different content of sugar and fat, in promoting obesity and related comorbidities as well as their impact on microbial load and gut microbiota composition/diversity. C57BL/6J mice were fed either a low-sugar, low-fat control diet (CT), a high-sugar diet (HS), a high-fat, high-sugar diet (HF/HS), or a high-fat diet (HF) for 8 wk. The impact of the different diets on obesity, glucose metabolism, inflammation, and oxidative and ER stress was determined. Diet-induced changes in the gut microbiota composition and density were also analyzed. HF diet-fed mice showed the highest body weight and fat mass gains and displayed the most impaired glucose and insulin profiles. HS, HF/HS, and HF diets differently affected hepatic cholesterol content and mRNA expression of several markers associated with immune cells, inflammation, oxidative and ER stress in several organs/tissues. In addition, HF diet feeding resulted in a decreased microbial load at the end of the experiment. When analyzing the gut microbiota composition, we found that HS, HF/HS, and HF diets induced specific changes in the abundance of certain bacterial taxa. This was not associated with a specific change in systemic inflammatory markers, but HS mice exhibited higher FGF21 plasma levels compared with HF diet-fed mice. Taken together, our results highlight that dietary intake of different macronutrients distinctively impacts the development of an obese/diabetic state and the regulation of metabolic inflammation in specific organs. We propose that these differences are not only obesity-driven but that changes in the gut microbiota composition may play a key role in this context.NEW & NOTEWORTHY To our knowledge, this study is the first to demonstrate that dietary macronutrients (i.e., sugar and fat) have an impact on fecal bacterial cell counting and quantitative microbiome profiling in mice. Yet, we demonstrate that dietary fat is the determining factor to promote obesity and diabetes progression, and local inflammation in different body sites. These observations can help to disentangle the conundrum of the detrimental effects of fat and sugar in our dietary habits.

Age and an obesogenic diet affect mouse behaviour in a sex-dependent manner.

Obesity is rising globally and is associated with neurodevelopmental and psychiatric disorders among children, adolescents and young adults. Whether obesity is the cause or the consequence of these disorders remains unclear. To examine the behavioural effects of obesity systematically, locomotion, anxiety and social behaviour were assessed in male and female C57Bl/6J mice using the open field, elevated plus maze and social preference task. First, the effects of age and sex were examined in control mice, before investigating post-weaning consumption of a high fat-high sugar diet commonly consumed in human populations with high rates of obesity. In the open field and elevated plus maze, locomotor activity and anxiety-related behaviours reduced with aging in both sexes, but with different sex-specific profiles. The high fat-high sugar diet reduced food and calorie intake and increased body mass and fat deposition in both sexes. In the open field, both male and female mice on the obesogenic diet showed reduced locomotion; whereas, in the elevated plus maze, only females fed with the obesogenic diet displayed reduced anxiety-related behaviours. Both male and female mice on the obesogenic diet had a significantly higher social preference index than the control group. In conclusion, the findings demonstrate that the behavioural effects of age and diet-induced obesity all depend on the sex of the mouse. This emphasises the importance of considering the age of the animal and including both sexes when assessing behavioural phenotypes arising from dietary manipulations.

Exogenous γ-aminobutyric acid improves the photosynthesis efficiency, soluble sugar contents, and mineral nutrients in pomegranate plants exposed to drought, salinity, and drought-salinity stresses.

BACKGROUND: γ-aminobutyric acid (GABA), as a regulator of many aspects of plant growth, has a pivotal role in improving plant stress resistance. However, few studies have focused on the use of GABA in increasing plants' resistance to interactional stresses, such as drought-salinity. Therefore, the focus of this study was to examine the effect of foliar application of GABA (0, 10, 20, and 40 mM) on growth indices and physio-biochemical parameters in plants of two pomegranate cultivars, 'Rabab' and 'Atabaki' exposed to drought, salinity, and drought-salinity. RESULTS: Under stress conditions, the photosynthetic capacity of two pomegranate cultivars, including transpiration rate, net photosynthetic rate, intercellular carbon dioxide concentration, stomatal conductance of water vapour, and mesophyll conductance, was significantly reduced. This resulted in a decrease in root morphological traits such as fresh and dry weight, diameter, and volume, as well as the fresh and dry weight of the aerial part of the plants. However, the application of GABA reversed the negative effects caused by stress treatments on growth parameters and maintained the photosynthetic capacity. GABA application has induced the accumulation of compatible osmolytes, including total soluble carbohydrate, starch, glucose, fructose, and sucrose, in charge of providing energy for cellular defense response against abiotic stresses. Analysis of mineral nutrients has shown that GABA application increases the absorption of potassium, potassium/sodium, magnesium, phosphorus, manganese, zinc, and iron. As concentration increased up to 40 mM, GABA prevented the uptake of toxic ions, sodium and chloride. CONCLUSIONS: These findings highlight the potential of GABA as a biostimulant strategy to enhance plant stress tolerance.

Ovarian inflammation mediated by Toll-like receptor 4 increased transcripts of maternal effect genes and decreased embryo development†.

Obese women are subfertile and have reduced assisted reproduction success, which may be due to reduced oocyte competence. We hypothesize that consumption of a high-fat/high-sugar diet induces ovarian inflammation, which is a primary contributor to decreased oocyte quality and pre-implantation embryo development. To test this hypothesis, C57BL/6 (B6) mice with a normal inflammatory response and C3H/HeJ (C3H) mice with a dampened inflammatory response due to dysfunctional Toll-like receptor 4 were fed either normal chow or high-fat/high-sugar diet. In both B6 and C3H females, high-fat/high-sugar diet induced excessive adiposity and hyperglycemia compared to normal chow-fed counterparts. Conversely, ovarian CD68 levels and oocyte expression of oxidative stress markers were increased when collected from B6 high-fat/high-sugar but not C3H high-fat/high-sugar mice. Following in vitro fertilization of in vivo matured oocytes, blastocyst development was decreased in B6-high-fat/high-sugar but not C3H high-fat/high-sugar mice. Expression of cumulus cell markers of oocyte quality were altered in both B6 high-fat/high-sugar and C3H high-fat/high-sugar. However, there were no diet-dependent differences in spindle abnormalities in either B6 or C3H mice, suggesting potential defects in cytoplasmic maturation. Indeed, there were significant increases in the abundance of maternal effect gene mRNAs in oocytes from only B6 high-fat/high-sugar mice. These differentially expressed genes encode proteins of the subcortical maternal complex and associated with mRNA metabolism and epigenetic modifications. These genes regulate maternal mRNA degradation at oocyte maturation, mRNA clearance at the zygotic genome activation, and methylation of imprinted genes suggesting a mechanism by which inflammation induced oxidative stress impairs embryo development.

Apoplastic sugar may be lost from grape berries and retrieved in pedicels.

In ripening grape (Vitis sp.) berries, the combination of rapid sugar import, apoplastic phloem unloading, and water discharge via the xylem creates a potential risk for apoplastic sugar to be lost from the berries. We investigated the likelihood of such sugar loss and a possible sugar retrieval mechanism in the pedicels of different Vitis genotypes. Infusion of D-glucose-1-13C or L-glucose-1-13C to the stylar end of attached berries demonstrated that both sugars can be leached from the berries, but only the nontransport sugar L-glucose moved beyond the pedicels. No 13C enrichment was found in peduncles and leaves. Genes encoding 10 sugar transporters were expressed in the pedicels throughout grape ripening. Using an immunofluorescence technique, we localized the sucrose transporter SUC27 to pedicel xylem parenchyma cells. These results indicate that pedicels possess the molecular machinery for sugar retrieval from the apoplast. Plasmodesmata were observed between vascular parenchyma cells in pedicels, and movement of the symplastically mobile dye carboxyfluorescein demonstrated that the symplastic connection is physiologically functional. Taken together, the chemical, molecular, and anatomical evidence gathered here supports the idea that some apoplastic sugar can be leached from grape berries and is effectively retrieved in a two-step process in the pedicels. First, sugar transporters may actively retrieve leached sugar from the xylem. Second, retrieved sugar may move symplastically to the pedicel parenchyma for local use or storage, or to the phloem for recycling back to the berry.

An inhibitory mechanism for suppressing high salt intake in Drosophila.

High concentrations of dietary salt are harmful to health. Like most animals, Drosophila melanogaster are attracted to foods that have low concentrations of salt, but show strong taste avoidance of high salt foods. Salt in known on multiple classes of taste neurons, activating Gr64f sweet-sensing neurons that drive food acceptance and 2 others (Gr66a bitter and Ppk23 high salt) that drive food rejection. Here we find that NaCl elicits a bimodal dose-dependent response in Gr64f taste neurons, which show high activity with low salt and depressed activity with high salt. High salt also inhibits the sugar response of Gr64f neurons, and this action is independent of the neuron's taste response to salt. Consistent with the electrophysiological analysis, feeding suppression in the presence of salt correlates with inhibition of Gr64f neuron activity, and remains if high salt taste neurons are genetically silenced. Other salts such as Na2SO4, KCl, MgSO4, CaCl2, and FeCl3 act on sugar response and feeding behavior in the same way. A comparison of the effects of various salts suggests that inhibition is dictated by the cationic moiety rather than the anionic component of the salt. Notably, high salt-dependent inhibition is not observed in Gr66a neurons-response to a canonical bitter tastant, denatonium, is not altered by high salt. Overall, this study characterizes a mechanism in appetitive Gr64f neurons that can deter ingestion of potentially harmful salts.

Different Effects of Sugars and Methods to Preserve Post-Thaw Functional Properties of Cryopreserved Caprine Spermatogonial Stem Cells.

The present study aimed to identify the effects of sugar and methods (slow freezing [SF] vs. fast freezing [FF]) on post-thaw in vitro functional characteristics of cryopreserved caprine spermatogonial stem cells (cSSCs) and the cells obtained from cryopreserved testis tissue of prepubertal Barbari bucks. For this, in experiment 1, cSSCs were isolated and cryopreserved by either SF or FF method with different non-permeable (sugars; trehalose [140 mm; 140T or 400 mm; 400T] and sucrose [140 mm; 140S or 400 mm; 400S]) or/and permeable (5% ethylene glycol [EG] and dimethyl sulfoxide) cryoprotectants. After 1 week of cryopreservation, the cSSCs were thawed and cultured for evaluation of their characteristics. Further, in experiment 2, the effectiveness of sugars (trehalose [140 mm] or sucrose [140 mm]) for cryopreservation of testicular tissues of prepubertal Barbari bucks using the SF or FF method was evaluated. After 1 week of cryopreservation, the tissues were thawed and cSSCs were isolated and cultured for 3 weeks. In both experiments, cSSCs were evaluated for recovery rate, proliferation, metabolic viability, senescence, and stemness markers' expression. The recovery rate was 1.3-, 1.3-, and 1.1-fold higher in the 140T group compared with EG, 140S, and 400S groups, respectively. Similarly, the expression of stemness markers (protein gene product 9.5 and octamer-binding transcription factor-4) was relatively higher in 140T group compared with the other groups. In experiment 2, the recovery rate of cells per unit tissue weight was significantly (p < 0.05) higher when cryopreserved using 140 mm trehalose compared with other groups. The results of immunocytochemical analyses imply the expression of pluripotent stem cell markers in cSSCs following cryopreservation. Overall, the outcome of the study demonstrates different effects of sugars and methods on post-thaw functional properties of cSSCs with superiority of 140 mm trehalose using SF method over other treatment groups. These results are important for ex vivo expansion and differentiation of cSSCs for fertility preservation and their other downstream applications.

Attractive targeted sugar bait: the pyrrole insecticide chlorfenapyr and the anti-malarial pharmaceutical artemether-lumefantrine arrest Plasmodium falciparum development inside wild pyrethroid-resistant Anopheles gambiae s.s. mosquitoes.

BACKGROUND: Attractive targeted sugar bait (ATSB) is a novel approach to vector control, offering an alternative mode of insecticide delivery via the insect alimentary canal, with potential to deliver a variety of compounds new to medical entomology and malaria control. Its potential to control mosquitoes was recently demonstrated in major field trials in Africa. The pyrrole chlorfenapyr is an insecticide new to malaria vector control, and through its unique mode of action-disruption of ATP mediated energy transfer in mitochondria-it may have direct action on energy transfer in the flight muscle cells of mosquitoes. It may also have potential to disrupt mitochondrial function in malarial parasites co-existing within the infected mosquito. However, little is known about the impact of such compounds on vector competence in mosquitoes responsible for malaria transmission. METHODS: In this study, ATSBs containing chlorfenapyr insecticide and, as a positive control, the anti-malarial drugs artemether/lumefantrine (A/L) were compared for their effect on Plasmodium falciparum development in wild pyrethroid-resistant Anopheles gambiae sensu stricto (s.s.) and for their capacity to reduce vector competence. Female mosquitoes were exposed to ATSB containing either sublethal dose of chlorfenapyr (CFP: 0.025%) or concentrations of A/L ranging from 0.4/2.4 mg/ml to 2.4/14.4 mg/ml, either shortly before or after taking infective blood meals. The impact of their component compounds on the prevalence and intensity of P. falciparum infection were compared between treatments. RESULTS: Both the prevalence and intensity of infection were significantly reduced in mosquitoes exposed to either A/L or chlorfenapyr, compared to unexposed negative control mosquitoes. The A/L dose (2.4/14.4 mg/ml) totally erased P. falciparum parasites: 0% prevalence of infection in female mosquitoes exposed compared to 62% of infection in negative controls (df = 1, χ2 = 31.23 p < 0.001). The dose of chlorfenapyr (0.025%) that killed < 20% females in ATSB showed a reduction in oocyte density of 95% per midgut (0.18/3.43 per midgut). CONCLUSION: These results are evidence that chlorfenapyr, in addition to its direct killing effect on the vector, has the capacity to block Plasmodium transmission by interfering with oocyte development inside pyrethroid-resistant mosquitoes, and through this dual action may potentiate its impact under field conditions.

5-Hydroxymethylfurfural multimers induce pseudo-allergic reaction through FcεRI at high doses.

Under acidic and high temperature conditions, 5-hydroxymethylfurfural (5-HMF) converted from sugar further produces dimers (Compound II) and trimers (Compound III). The polymers were less reported, and sensitization effect of them was reported in this study. Compounds II and III induced the local and systemic anaphylaxis effect in passive cutaneous anaphylaxis mice model and activated RBL-2H3 cell inducing [Ca2+ ] mobilization, resulting in the release of ß-hexosaminidase and histamine in vitro. The gene knockdown assay figured out that Compounds II and III induced degranulation through FcεRI. Further, Compounds II and III had a certain affinity with FcεRI by cell membrane chromatography and may combine on the "proline sandwich" structure indicated by molecular docking. All above suggested Compounds II and III can induce pseudo-allergic reaction through FcεRI in vivo and in vitro. Our work provides basic research to prove that the newly discovered 5-HMF transformants, Compounds II and III, induce pseudo-allergic reaction in vitro and in vivo through FcεRI, which is different pathway from 5-HMF. In foods with high sugar content, the sensitization of Compounds II and III needs more attention. In high-sugar foods and medicines, especially traditional Chinese medicine injections, the content of transformants needs to be detected.

Effects of cadmium stress on the morphology, physiology, cellular ultrastructure, and BvHIPP24 gene expression of sugar beet (Beta vulgaris L.).

To clarify the mechanism of the response of sugar beet (Beta vulgaris L.) to cadmium (Cd) stress, this study investigated changes in the phenotype, physiological indexes, and subcellular structure of B. vulgaris under Cd treatment and the transcriptional pattern of the BvHIPP24 gene (a heavy metal-associated isoprenylated plant protein involved in heavy metal detoxification). The plant height and shoot and root growth of B. vulgaris seedlings were inhibited to some extent under 0.5 and 1 mM Cd, with gradually wilting and yellowing of leaves and dark brown roots. When the Cd concentration was increased, malondialdehyde content and the activities of peroxidase, superoxide dismutase, and glutathione S-transferase increased differentially. qPCR indicated that the expression of BvHIPP24 was induced by different concentrations of Cd. Although transmission electron microscopy revealed damage to nuclei, mitochondria, and chloroplasts, B. vulgaris exhibited strong adaptability to 0.5 mM Cd according to a comprehensive analysis using the membership function. The results showed that B. vulgaris may reduce cell damage and improve its Cd tolerance by regulating functional gene expression and antioxidant enzymes. This study increases our understanding of the Cd-tolerance mechanism of B. vulgaris and provides insights into the use of B. vulgaris in Cd bioremediation.

Sugar beet is a novel energy crop with superior characteristics for both heavy metal phytoremediation and biomass energy development. This work is the first to investigate both the morphological, physiological, and ultrastructural response of sugar beet to cadmium stress and the induction of a functional metallochaperone gene by cadmium. This study explains the cadmium tolerance mechanism of sugar beet based on a comprehensive evaluation and provides an important theoretical basis for further application of beet in heavy metal bioremediation.

First Synthesis of DBU-Conjugated Cationic Carbohydrate Derivatives and Investigation of Their Antibacterial and Antifungal Activity.

The emergence of drug-resistant bacteria and fungi represents a serious health problem worldwide. It has long been known that cationic compounds can inhibit the growth of bacteria and fungi by disrupting the cell membrane. The advantage of using such cationic compounds is that the microorganisms would not become resistant to cationic agents, since this type of adaptation would mean significantly altering the structure of their cell walls. We designed novel, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)-derived amidinium salts of carbohydrates, which may be suitable for disturbing the cell walls of bacteria and fungi due to their quaternary ammonium moiety. A series of saccharide-DBU conjugates were prepared from 6-iodo derivatives of d-glucose, d-mannose, d-altrose and d-allose by nucleophilic substitution reactions. We optimized the synthesis of a d-glucose derivative, and studied the protecting group free synthesis of the glucose-DBU conjugates. The effect of the obtained quaternary amidinium salts against Escherichia coli and Staphylococcus aureus bacterial strains and Candida albicans yeast was investigated, and the impact of the used protecting groups and the sugar configuration on the antimicrobial activity was analyzed. Some of the novel sugar quaternary ammonium compounds with lipophilic aromatic groups (benzyl and 2-napthylmethyl) showed particularly good antifungal and antibacterial activity.

Galectin-9 in Gastroenterological Cancer.

Immunochemotherapy has become popular in recent years. The detailed mechanisms of cancer immunity are being elucidated, and new developments are expected in the future. Apoptosis allows tissues to maintain their form, quantity, and function by eliminating excess or abnormal cells. When apoptosis is inhibited, the balance between cell division and death is disrupted and tissue homeostasis is impaired. This leads to dysfunction and the accumulation of genetically abnormal cells, which can contribute to carcinogenesis. Lectins are neither enzymes nor antibodies but proteins that bind sugar chains. Among soluble endogenous lectins, galectins interact with cell surface sugar chains outside the cell to regulate signal transduction and cell growth. On the other hand, intracellular lectins are present at the plasma membrane and regulate signal transduction by regulating receptor-ligand interactions. Galectin-9 expressed on the surface of thymocytes induces apoptosis of T lymphocytes and plays an essential role in immune self-tolerance by negative selection in the thymus. Furthermore, the administration of extracellular galectin-9 induces apoptosis of human cancer and immunodeficient cells. However, the detailed pharmacokinetics of galectin-9 in vivo have not been elucidated. In addition, the cell surface receptors involved in galectin-9-induced apoptosis of cancer cells have not been identified, and the intracellular pathways involved in apoptosis have not been fully investigated. We have previously reported that galectin-9 induces apoptosis in various gastrointestinal cancers and suppresses tumor growth. However, the mechanism of galectin-9 and apoptosis induction in gastrointestinal cancers and the detailed mechanisms involved in tumor growth inhibition remain unknown. In this article, we review the effects of galectin-9 on gastrointestinal cancers and its mechanisms.

[Antidepressant mechanism of Shenling Kaixin Granules based on BDNF/TrkB/CREB pathway].

To investigate the antidepressant mechanism of Shenling Kaixin Granules(SLKX) in treating chronic unpredictable mild stress(CUMS) model rats. Ninety male SD rats were randomly divided into control group, model group, Shugan Jieyu Capsules(110 mg·kg~(-1)) group and SLKX low-(90 mg·kg~(-1)), medium-(180 mg·kg~(-1)), and high-dose(360 mg·kg~(-1)) groups. Depression rat model was replicated by CUMS method. After treatment, the behavioral changes of rats were evaluated by sugar preference, open field, elevated cross maze and forced swimming experiments. The contents of interleukin 1 beta(IL-1ß), tumor necrosis factor α(TNF-α), brain-derived neurotrophic factor(BDNF) and 5-hydroxytryptamine(5-HT) in serum were determined by enzyme linked immunosorbent assay(ELISA), and the activities of superoxide dismutase(SOD) and catalase(CAT) in hippocampal CA1 region were also detected. Pathological changes in hippocampal CA1 region were detected by hematoxylin-eosin(HE) staining, and Western blot was used to determine the expression of nerve growth factor(NGF), BDNF, phospho-tyrosine kinase receptor(p-TrkB)/TrkB, phospho-cAMP-response element binding protein(p-CREB)/CREB, nuclear factor E2 related factor 2(Nrf2), heme oxygenase 1(HO-1), B-cell lymphoma-2(Bcl-2)/Bcl-2 associated X protein(Bax) and caspase-3 in hippocampal CA1 region. RESULTS:: showed that compared with the control group, the model group had decreased sugar preference, reduced number of entries and time spent in the center of open field and shortened total distance of movement, reduced number of entries and proportion of time spent in open arm, and increased number and time of immobility in forced swimming experiment. Additionally, the serum contents of IL-1ß and TNF-α and the expression of caspase-3 were higher, while the contents of BDNF and 5-HT, the activities of SOD and CAT in hippocampal CA1 region, the expressions of NGF, BDNF, p-TrkB/TrkB, p-CREB/CREB, HO-1 and Bcl-2/Bax, and the Nrf2 nuclear translocation were lower in model group than in control group. Compared with the conditions in model group, the sugar preference, the number of entries and time spent in the center of open, total distance of movement, and the number of entries and proportion of time spent in open arm in treatment groups were increased while the number and time of immobility in forced swimming experiment were decreased; the serum contents of IL-1ß and TNF-α and the expression of caspase-3 were down regulated, while the contents of BDNF and 5-HT, the activities of SOD and CAT in hippocampal CA1 region, the expressions of NGF, BDNF, p-TrkB/TrkB, p-CREB/CREB, HO-1, Bcl-2/Bax, and Nrf2 nuclear translocation were enhanced. In conclusion, SLKX might regulate the Nrf2 nucleus translocation by activating BDNF/TrkB/CREB pathway, lower oxidative stress damage in hippocampus, inhibit caspase-3 activity, and reduce apoptosis of hippocampal nerve cells, thereby playing an antidepressant role.

Early unhealthy eating habits underlie morpho-functional changes in the liver and adipose tissue in male rats.

Early-life consumption of high-fat and sugar-rich foods is recognized as a major contributor for the onset of metabolic dysfunction and its related disorders, including diabetes and nonalcoholic fatty liver disease. The lifelong impact of early unhealthy eating habits that start at younger ages remains unclear. Therefore, to better understand the effects of diet, it is essential to evaluate the structural and functional changes induced in metabolic organs and potential mechanisms underlying those changes. To investigate the long-term effects of eating habits, young male rats were exposed to high-sugar and high-energy diets. After 14 weeks, body composition was assessed, and histopathological changes were analyzed in the liver and adipose tissue. Serum biochemical parameters were also determined. Expression of inflammatory markers in the liver was evaluated by immunohistochemistry. Our results revealed that serum levels of glucose, creatinine, aspartate transaminase (AST), alanine transaminase (ALT), and lipid profile were increased in rats red high-sugar and high-energy diets. Histopathological alterations were observed, including abnormal hepatocyte organization and lipid droplet accumulation in the liver, and abnormal structure of adipocytes. In both unhealthy diet groups, hepatic expression of Toll-like receptor 4 (TLR4), cyclooxygenase 2 (COX-2), and E-selectin were increased, as well as a biomarker of oxidative stress. Together, our data demonstrated that unhealthy diets induced functional and structural changes in the metabolic organs, suggesting that proinflammatory and oxidative stress mechanisms trigger the hepatic alterations and metabolic dysfunction.

TOR and SnRK1 fine tune SPEECHLESS transcription and protein stability to optimize stomatal development in response to exogenously supplied sugar.

In Arabidopsis, the differentiation of epidermal cells into stomata is regulated by endogenous and environmental signals. Sugar is required for plant epidermal cell proliferation and differentiation. However, it is unclear how epidermal cells maintain division and differentiation to generate proper amounts of stomata in response to different sugar availability. Here, we show that two evolutionarily conserved kinase Snf1-related protein kinase 1 (SnRK1) and Target of rapamycin (TOR) play critical roles in the regulation of stomatal development under different sugar availability. When plants are grown on a medium containing 1% sucrose, sucrose-activated TOR promotes the stomatal development by inducing the expression of SPEECHLESS (SPCH), a master regulator of stomatal development. SnRK1 promotes stomatal development through phosphorylating and stabilizing SPCH. However, under the high sucrose conditions, the highly accumulated trehalose-6-phosphate (Tre6P) represses the activity of KIN10, the catalytic α-subunit of SnRK1, by reducing the interaction between KIN10 and its upstream kinase, consequently promoting SPCH degradation and inhibiting stomatal development. Our findings revealed that TOR and SnRK1 finely regulate SPCH expression and protein stability to optimize the stomatal development in response to exogenously supplied sugar.

IL10/AMPK pathway was associated with the hippocampal anti-inflammatory response to high-sugar and high-fat diet withdrawal.

OBJECTIVE: The present experimental study aimed to evaluate the effect of consuming an obesogenic diet (OD) on serum and hippocampal inflammation and proteins related to energy metabolism, alongside, we evaluated how the same parameters responded to an OD withdrawal. SUBJECTS: Thirty male 60-days-old Wistar rats were used. METHODS: The control group (n = 10) was fed the control diet across the whole experiment. The remaining animals were fed a high-sugar/high-fat (HSHF) diet for 30 days (n = 20) and half of them were placed on the control diet for 48 h (n = 10) afterwards. RESULTS: OD intake decreased hippocampal AMPK phosphorylation, although, it did not increase serum inflammation and only increased hippocampal pNFκBp65 levels without any increase in the cytokines assessed. Moreover, OD withdrawal led to higher inflammatory markers in the serum and hippocampus and higher hippocampal AMPK phosphorylation. The mediation models applied suggested that the effect of OD withdrawal on hippocampal inflammation was driven by serum inflammation, which activated the hippocampal IL10/AMPK anti-inflammatory pathway as a response. CONCLUSION: Our analyses suggest that OD withdrawal increases serum inflammation with hippocampal consequent inflammatory alterations. Despite the general assumption that improving diet improves health, this may not be immediate.

Effort-based decision making in response to high-dose androgens: role of dopamine receptors.

INTRODUCTION: Anabolic-androgenic steroids (AAS) are performance-enhancing drugs used by both world-class and rank-and-file athletes. AAS abuse has been linked with risky decision-making, ranging from drunk driving to abusing multiple drugs. Our lab uses operant behavior in rats to test the effects of AAS (testosterone) on decision making. In our previous study, testosterone caused rats to work harder for food reward during an effort discounting (ED) task. ED is sensitive to dopamine in the nucleus accumbens, and AAS alter accumbens dopamine receptor expression. Accordingly, we determined if testosterone increases response to dopamine receptor antagonists during ED. METHODS: Rats were treated chronically with high-dose testosterone (7.5 mg/kg; n = 9) or vehicle (n = 9). We measured baseline preference for the large reward in an ED task, where rats choose between a small easy reward (one lever press for one sugar pellet) and a large difficult reward (2, 5, 10, or 15 presses for three pellets). Preference for the large reward was measured after administration of D1-like (SCH23390, 0.01 mg/kg) or D2-like (eticlopride, 0.06 mg/kg) receptor antagonists. RESULTS: At baseline, testosterone- and vehicle-treated rats showed similar preference for the large reward lever (FR5, testosterone: 68.6 ± 9.7% and vehicle: 85.7 ± 2.5%). SCH23390 reduced large reward preference significantly in both groups (FR5, testosterone: 41.3 ± 9.2%; vehicle: 49.1 ± 8.2%; F(1,16) = 17.7; P < 0.05). Eticlopride decreased large reward preference in both groups, but more strongly in testosterone-treated rats (FR5: testosterone: 37.0 ± 9.7%; vehicle: 56.3 ± 7.8%; F(1,16) = 35.3; P < 0.05). CONCLUSION: Testosterone increases response to dopamine D2-like receptor blockade, and this contributes to previously observed changes in decision-making behaviors.