MRGPRB2/X2 and the analogous effects of its agonist and antagonist in DSS-induced colitis in mice.

The mast cell receptor Mrgprb2, a mouse orthologue of human Mrgprx2, is known as an inflammatory receptor and its elevated expression is associated with various diseases such as ulcerative colitis. We aimed to elucidate the role of Mrgprb2/x2 and the effect of its ligands on a chemically induced murine colitis model. We showed that in Mrgprb2-/- mice, there is a differential regulation of cytokine releases in the blood plasma and severe colonic damages after DSS treatment. Unexpectedly, we demonstrated that known Mrgprb2/x2 agonists (peptide P17, P17 analogues and CST-14) and antagonist (GE1111) similarly increased the survival rate of WT mice subjected to 4% DSS-induced colitis, ameliorated the colonic damages of 2.5% DSS-induced colitis, restored major protein mRNA expression involved in colon integrity, reduced CD68+ and F4/80+ immune cell infiltration and restored cytokine levels. Collectively, our findings highlight the eminent role of Mrpgrb2/x2 in conferring a beneficial effect in the colitis model, and this significance is demonstrated by the heightened severity of colitis with altered cytokine releases and inflammatory immune cell infiltration observed in the Mrgprb2 knockout mice. Elevated expression of Mrgprb2 in WT colitis murine models may represent the organism's adaptive protective mechanism since Mrgprb2 knockout results in severe colitis. On the other hand, both agonist and antagonist of Mrgprb2 analogously mitigated the severity of colitis in DSS-induced colitis model by altering Mrgprb2 expression, immune cell infiltration and inflammatory cytokine releases.

Loss of the Secretin Receptor Impairs Renal Bicarbonate Excretion and Aggravates Metabolic Alkalosis in Mice during Acute Base-Loading.

SIGNIFICANCE STATEMENT: During acute base excess, the renal collecting duct ß -intercalated cells ( ß -ICs) become activated to increase urine base excretion. This process is dependent on pendrin and cystic fibrosis transmembrane regulator (CFTR) expressed in the apical membrane of ß -ICs. The signal that leads to activation of this process was unknown. Plasma secretin levels increase during acute alkalosis, and the secretin receptor (SCTR) is functionally expressed in ß -ICs. We find that mice with global knockout for the SCTR lose their ability to acutely increase renal base excretion. This forces the mice to lower their ventilation to cope with this challenge. Our findings suggest that secretin is a systemic bicarbonate-regulating hormone, likely being released from the small intestine during alkalosis. BACKGROUND: The secretin receptor (SCTR) is functionally expressed in the basolateral membrane of the ß -intercalated cells of the kidney cortical collecting duct and stimulates urine alkalization by activating the ß -intercalated cells. Interestingly, the plasma secretin level increases during acute metabolic alkalosis, but its role in systemic acid-base homeostasis was unclear. We hypothesized that the SCTR system is essential for renal base excretion during acute metabolic alkalosis. METHODS: We conducted bladder catheterization experiments, metabolic cage studies, blood gas analysis, barometric respirometry, perfusion of isolated cortical collecting ducts, immunoblotting, and immunohistochemistry in SCTR wild-type and knockout (KO) mice. We also perfused isolated rat small intestines to study secretin release. RESULTS: In wild-type mice, secretin acutely increased urine pH and pendrin function in isolated perfused cortical collecting ducts. These effects were absent in KO mice, which also did not sufficiently increase renal base excretion during acute base loading. In line with these findings, KO mice developed prolonged metabolic alkalosis when exposed to acute oral or intraperitoneal base loading. Furthermore, KO mice exhibited transient but marked hypoventilation after acute base loading. In rats, increased blood alkalinity of the perfused upper small intestine increased venous secretin release. CONCLUSIONS: Our results suggest that loss of SCTR impairs the appropriate increase of renal base excretion during acute base loading and that SCTR is necessary for acute correction of metabolic alkalosis. In addition, our findings suggest that blood alkalinity increases secretin release from the small intestine and that secretin action is critical for bicarbonate homeostasis.

Amygdala neural ensemble mediates mouse social investigation behaviors.

Innate social investigation behaviors are critical for animal survival and are regulated by both neural circuits and neuroendocrine factors. Our understanding of how neuropeptides regulate social interest, however, is incomplete at the current stage. In this study, we identified the expression of secretin (SCT) in a subpopulation of excitatory neurons in the basolateral amygdala. With distinct molecular and physiological features, BLASCT+ cells projected to the medial prefrontal cortex and were necessary and sufficient for promoting social investigation behaviors, whilst other basolateral amygdala neurons were anxiogenic and antagonized social behaviors. Moreover, the exogenous application of secretin effectively promoted social interest in both healthy and autism spectrum disorder model mice. These results collectively demonstrate a previously unrecognized group of amygdala neurons for mediating social behaviors and suggest promising strategies for social deficits.

Novel small molecule MRGPRX2 antagonists inhibit a murine model of allergic reaction.

BACKGROUND: Activation of Mas-related G protein-coupled receptor X2 (MRGPRX2) is a crucial non-IgE pathway for mast cell activation associated with allergic reactions and inflammation. Only a few peptides and small compounds targeting MRGPRX2 have been reported, with limited information on their pharmacologic activity. OBJECTIVE: We sought to develop novel small molecule MRGPRX2 antagonists to treat MRGPRX2-mediated allergies and inflammation. METHODS: A computational approach was used to design novel small molecules as MRGPRX2 antagonists. The short-listed molecules were synthesized and characterized by liquid chromatography and mass spectrometry as well as nuclear magnetic resonance. Inhibitory activity on MRGPRX2 signaling was assessed in vitro by using functional bioassays (ß-hexosaminidase, calcium flux, and chemokine synthesis) and receptor activation assays (ß-arrestin recruitment and Western blot analysis) in human LAD-2 mast cells and HTLA cells. In vivo effects of the novel MRGPRX2 antagonists were assessed using a mouse model of acute allergy and systemic anaphylaxis. RESULTS: The novel small molecules demonstrated higher binding affinity with MRGPRX2 in the docking study. The half-maximal inhibitory concentration is in the low micromolar range (5-21 µM). The small molecules inhibited not only the early phase of mast cell activation but also the late phase, associated with chemokine and prostaglandin release. Further, Western blot analysis revealed inhibition of downstream phospholipase C-γ, extracellular signal-regulated protein kinase 1/2, and Akt signaling pathway. Moreover, in the mouse models of allergies, small molecule administration effectively blocks acute, systemic allergic reactions and inflammation and prevents systemic anaphylaxis. CONCLUSION: The small molecules might hold a significant therapeutic promise to treat MRGPRX2-mediated allergies and inflammation.

PACAP/GCGa Is an Important Modulator of the Amphioxus CNS-Hatschek's Pit Axis, the Homolog of the Vertebrate Hypothalamic-Pituitary Axis in the Basal Chordates.

The Hatschek's pit in the cephalochordate amphioxus, an invertebrate deuterostome basal to chordates is suggested to be the functional homolog structure of the vertebrate adenohypophysis based on anatomy and expression of homologous neuroendocrine genes. However, the endocrine potential of the cephalochordate Hatschek's pit remains to be demonstrated as well as the physiological actions of the secreted neuropeptides. In this study, we have explored the distribution and characterize the potential function of the amphioxus PACAP/GCG precursor, which is the ortholog of the hypothalamic PACAP neuropeptide in vertebrates. In amphioxi, two PACAP/GCG transcripts PACAP/GCGa and PACAP/GCGbc that are alternative isoforms of a single gene with different peptide coding potentials were isolated. Immunofluorescence staining detected their expression around the nucleus of Rohde, supporting that this structure may be homologous of the neurosecretory cells of the vertebrate hypothalamus where abundant PACAP is found. PACAP/GCGa was also detected in the infundibulum-like downgrowth approaching the Hatschek's pit, indicating diffusion of PACAP/GCGa from the CNS to the pit via the infundibulum-like downgrowth. Under a high salinity challenge, PACAP/GCGa was upregulated in amphioxi head and PACAP/GCGa treatment increased expression of GHl in Hatschek's pit in a dose-dependent manner, suggesting that PACAP/GCGa may be involved in the regulation of GHl via hypothalamic-pituitary (HP)-like axis similar as in the vertebrates. Our results support that the amphioxus Hatschek's pit is likely to be the functional homolog of pituitary gland in vertebrates.

Hydroxysafflor yellow A triggered a fast-to-slow muscle fiber-type conversion via regulating FoxO1 in myocytes.

Hydroxysafflor yellow A (HSYA) is the main bioactive component of safflower and has been reported to have significant health-promoting abilities. However, the regulation of HSYA on different types of skeletal myofibers is largely unknown. Here, in vitro experiments found that the water extract of safflower could significantly increase MyHC I, MB and Tnni1 mRNA expression while downregulating MyHC IIb mRNA expression. Furthermore, HSYA triggered fast-to-slow fiber-type switching and increased gene expression related to mitochondrial biosynthesis both in vitro and in vivo. Autodock analyses proved that FoxO1 is a potential target of HSYA, and qRT-PCR and western blotting further showed that HSYA significantly promoted the activation of the FoxO1 signaling pathway. Additionally, the levels of PGC1α, downstream of FoxO1, also significantly increased after HSYA treatment. Together, our findings suggested that HSYA triggered a fast-to-slow myofiber-type shift through the FoxO1 signaling pathway.

P17 induces chemotaxis and differentiation of monocytes via MRGPRX2-mediated mast cell-line activation.

BACKGROUND: P17, a peptide isolated from Tetramorium bicarinatum ant venom, is known to induce an alternative phenotype of human monocyte-derived macrophages via activation of an unknown G protein-coupled receptor (GPCR). OBJECTIVE: We sought to investigate the mechanism of action and the immunomodulatory effects of P17 mediated through MRGPRX2 (Mas-related G protein-coupled receptor X2). METHODS: To identify the GPCR for P17, we screened 314 GPCRs. Upon identification of MRGPRX2, a battery of in silico, in vitro, ex vivo, and in vivo assays along with the receptor mutation studies were performed. In particular, to investigate the immunomodulatory actions, we used ß-hexosaminidase release assay, cytokine releases, quantification of mRNA expression, cell migration and differentiation assays, immunohistochemical labeling, hematoxylin and eosin, and immunofluorescence staining. RESULTS: P17 activated MRGPRX2 in a dose-dependent manner in ß-arrestin recruitment assay. In LAD2 cells, P17 induced calcium and ß-hexosaminidase release. Quercetin- and short hairpin RNA-mediated knockdown of MRGPRX2 reduced P17-evoked ß-hexosaminidase release. In silico and in vitro mutagenesis studies showed that residue Lys8 of P17 formed a cation-π interaction with the Phe172 of MRGPRX2 and [Ala8]P17 lost its activity partially. P17 activated LAD2 cells to recruit THP-1 and human monocytes in Transwell migration assay, whereas MRGPRX2-impaired LAD2 cells cannot. In addition, P17-treated LAD2 cells stimulated differentiation of THP-1 and human monocytes, as indicated by the enhanced expression of macrophage markers cluster of differentiation 11b and TNF-α by quantitative RT-PCR. Immunohistochemical and immunofluorescent staining suggested monocyte recruitment in mice ears injected with P17. CONCLUSIONS: Our data provide novel structural information regarding the interaction of P17 with MRGPRX2 and intracellular pathways for its immunomodulatory action.

GIP receptor suppresses PAC1receptor-mediated neuronal differentiation via formation of a receptor heterocomplex.

Pituitary adenylate cyclase-activating peptide (PACAP) receptor (PAC1R) is a class B Gprotein-coupled receptor (GPCR) that is widely expressed in the human body and is involved in neuronal differentiation. As class B GPCRs are known to form heterocomplexes with family members, we hypothesized that PAC1R mediates neuronal differentiation through interaction with a class B GPCR. We used the BRET assay to identify potential interactions between PAC1R and 11 class B GPCRs. Gastric inhibitory polypeptide receptor (GIPR) and secretin receptor were identified as putative binding partners of PAC1R. The effect of heterocomplex formation by PAC1R on receptor activation was evaluated with the cyclic (c)AMP, luciferase reporter, and calcium signaling assays; and the effects on receptor internalization and subcellular localization were examined by confocal microscopy. The results suggested he PAC1R/GIPR heterocomplex suppressed signaling events downstream of PAC1R, including cAMP production, serum response element and calcium signaling, and ß-arrestin recruitment. Protein-protein interaction was analyzed in silico, and induction of neuronal differentiation by the PAC1R heterocomplex was assessed in SH-SY5Y neuronal cells by measure the morphological changes and marker genes expression by real-time quantitative PCR and western blot. Over-expression of GIPR suppressed PACAP/PAC1R-mediated neuronal differentiation and the differentiation markers expression in SH-SY5Y cells. GIPR regulates neuronal differentiation through heterocomplex formation with PAC1R.

Predictable modulation of cancer treatment outcomes by the gut microbiota.

The gut microbiota has the potential to influence the efficacy of cancer therapy. Here, we investigated the contribution of the intestinal microbiome on treatment outcomes in a heterogeneous cohort that included multiple cancer types to identify microbes with a global impact on immune response. Human gut metagenomic analysis revealed that responder patients had significantly higher microbial diversity and different microbiota compositions compared to non-responders. A machine-learning model was developed and validated in an independent cohort to predict treatment outcomes based on gut microbiota composition and functional repertoires of responders and non-responders. Specific species, Bacteroides ovatus and Bacteroides xylanisolvens, were positively correlated with treatment outcomes. Oral gavage of these responder bacteria significantly increased the efficacy of erlotinib and induced the expression of CXCL9 and IFN-γ in a murine lung cancer model. These data suggest a predictable impact of specific constituents of the microbiota on tumor growth and cancer treatment outcomes with implications for both prognosis and therapy.

A crustacean annotated transcriptome (CAT) database.

BACKGROUND: Decapods are an order of crustaceans which includes shrimps, crabs, lobsters and crayfish. They occur worldwide and are of great scientific interest as well as being of ecological and economic importance in fisheries and aquaculture. However, our knowledge of their biology mainly comes from the group which is most closely related to crustaceans - insects. Here we produce a de novo transcriptome database, crustacean annotated transcriptome (CAT) database, spanning multiple tissues and the life stages of seven crustaceans. DESCRIPTION: A total of 71 transcriptome assemblies from six decapod species and a stomatopod species, including the coral shrimp Stenopus hispidus, the cherry shrimp Neocaridina davidi, the redclaw crayfish Cherax quadricarinatus, the spiny lobster Panulirus ornatus, the red king crab Paralithodes camtschaticus, the coconut crab Birgus latro, and the zebra mantis shrimp Lysiosquillina maculata, were generated. Differential gene expression analyses within species were generated as a reference and included in a graphical user interface database at http://cat.sls.cuhk.edu.hk/. Users can carry out gene name searches and also access gene sequences based on a sequence query using the BLAST search function. CONCLUSIONS: The data generated and deposited in this database offers a valuable resource for the further study of these crustaceans, as well as being of use in aquaculture development.

Loss of secretin results in systemic and pulmonary hypertension with cardiopulmonary pathologies in mice.

More than 1 billion people globally are suffering from hypertension, which is a long-term incurable medical condition that can further lead to dangerous complications and death if left untreated. In earlier studies, the brain-gut peptide secretin (SCT) was found to be able to control blood pressure by its cardiovascular and pulmonary effects. For example, serum SCT in patients with congestive heart failure was one-third of the normal level. These observations strongly suggest that SCT has a causal role in blood pressure control, and in this report, we used constitutive SCT knockout (SCT-/-) mice and control C57BL/6N mice to investigate differences in the morphology, function, underlying mechanisms and response to SCT treatment. We found that SCT-/- mice suffer from systemic and pulmonary hypertension with increased fibrosis in the lungs and heart. Small airway remodelling and pulmonary inflammation were also found in SCT-/- mice. Serum NO and VEGF levels were reduced and plasma aldosterone levels were increased in SCT-/- mice. Elevated cardiac aldosterone and decreased VEGF in the lungs were observed in the SCT-/- mice. More interestingly, SCT replacement in SCT-/- mice could prevent the development of heart and lung pathologies compared to the untreated group. Taken together, we comprehensively demonstrated the critical role of SCT in the cardiovascular and pulmonary systems and provide new insight into the potential role of SCT in the pathological development of cardiopulmonary and cardiovascular diseases.

Role of SCTR/AT1aR heteromer in mediating ANGII-induced aldosterone secretion.

The involvement of secretin (SCT) and its receptor (SCTR) in angiotensin II (ANGII)-mediated osmoregulation by forming SCTR/ angiotensin II type 1 receptor (AT1R) heteromer is well established. In this study, we demonstrated that SCTR/AT1R complex can mediate ANGII-induced aldosterone secretion/release through potentiating calcium mobilization. Through IHC and cAMP studies, we showed the presence of functional SCTR and AT1R in the primary zona glomerulosa (ZG) cells of C57BL/6N (C57), and functional AT1R and non-functional SCTR in SCTR knockout (SCTR-/-) mice. Calcium mobilization studies revealed the important role of SCTR on ANGII-mediated calcium mobilization in adrenal gland. The fluo4-AM loaded primary adrenal ZG cells from the C57 mice displayed a dose-dependent increase in intracellular calcium influx ([Ca2+]i) when exposed to ANGII but not from the SCTR-/- ZG cells. Synthetic SCTR transmembrane (TM) peptides STM-II/-IV were able to alter [Ca2+]i in C57 mice, but not the mice with mutated STM-II/-IV (STM-IIm/IVm) peptides. Through enzyme immunoassay (EIA), we measured the aldosterone release from primary ZG cells of both C57 and SCTR-/- mice by exposing them to ANGII (10nM). SCTR-/- ZG cells showed impaired ANGII-induced aldosterone secretion compared to the C57 mice. TM peptide, STM-II hindered the aldosterone secretion in ZG cells of C57 mice. These findings support the involvement of SCTR/AT1R heterodimer complex in aldosterone secretion/release through [Ca2+]i.

Muscle-generated BDNF is a sexually dimorphic myokine that controls metabolic flexibility.

The ability of skeletal muscle to switch between lipid and glucose oxidation for ATP production during metabolic stress is pivotal for maintaining systemic energy homeostasis, and dysregulation of this metabolic flexibility is a dominant cause of several metabolic disorders. However, the molecular mechanism that governs fuel selection in muscle is not well understood. Here, we report that brain-derived neurotrophic factor (BDNF) is a fasting-induced myokine that controls metabolic reprograming through the AMPK/CREB/PGC-1α pathway in female mice. Female mice with a muscle-specific deficiency in BDNF (MBKO mice) were unable to switch the predominant fuel source from carbohydrates to fatty acids during fasting, which reduced ATP production in muscle. Fasting-induced muscle atrophy was also compromised in female MBKO mice, likely a result of autophagy inhibition. These mutant mice displayed myofiber necrosis, weaker muscle strength, reduced locomotion, and muscle-specific insulin resistance. Together, our results show that muscle-derived BDNF facilitates metabolic adaption during nutrient scarcity in a gender-specific manner and that insufficient BDNF production in skeletal muscle promotes the development of metabolic myopathies and insulin resistance.

Mining, analyzing, and integrating viral signals from metagenomic data.

BACKGROUND: Viruses are important components of microbial communities modulating community structure and function; however, only a couple of tools are currently available for phage identification and analysis from metagenomic sequencing data. Here we employed the random forest algorithm to develop VirMiner, a web-based phage contig prediction tool especially sensitive for high-abundances phage contigs, trained and validated by paired metagenomic and phagenomic sequencing data from the human gut flora. RESULTS: VirMiner achieved 41.06% ± 17.51% sensitivity and 81.91% ± 4.04% specificity in the prediction of phage contigs. In particular, for the high-abundance phage contigs, VirMiner outperformed other tools (VirFinder and VirSorter) with much higher sensitivity (65.23% ± 16.94%) than VirFinder (34.63% ± 17.96%) and VirSorter (18.75% ± 15.23%) at almost the same specificity. Moreover, VirMiner provides the most comprehensive phage analysis pipeline which is comprised of metagenomic raw reads processing, functional annotation, phage contig identification, and phage-host relationship prediction (CRISPR-spacer recognition) and supports two-group comparison when the input (metagenomic sequence data) includes different conditions (e.g., case and control). Application of VirMiner to an independent cohort of human gut metagenomes obtained from individuals treated with antibiotics revealed that 122 KEGG orthology and 118 Pfam groups had significantly differential abundance in the pre-treatment samples compared to samples at the end of antibiotic administration, including clustered regularly interspaced short palindromic repeats (CRISPR), multidrug resistance, and protein transport. The VirMiner webserver is available at http://sbb.hku.hk/VirMiner/ . CONCLUSIONS: We developed a comprehensive tool for phage prediction and analysis for metagenomic samples. Compared to VirSorter and VirFinder-the most widely used tools-VirMiner is able to capture more high-abundance phage contigs which could play key roles in infecting bacteria and modulating microbial community dynamics. TRIAL REGISTRATION: The European Union Clinical Trials Register, EudraCT Number: 2013-003378-28 . Registered on 9 April 2014.

Secretin Prevents Apoptosis in the Developing Cerebellum Through Bcl-2 and Bcl-xL.

Secretin (SCT) is involved in a variety of physiological processes and has been implicated in preventing apoptosis during brain development. However, little is known about the molecular mechanism underlying its neuroprotective effects. The B cell lymphoma 2 (Bcl-2) family proteins, such as Bcl-2 and Bcl-xL, determine the commitment of neurons to apoptosis. In SCT knockout mice, we found reduced transcript levels of anti-apoptotic genes Bcl-2 and Bcl-xL, but not of pro-apoptotic gene Bax, in the developing cerebellum. SCT treatment on ex vivo cultured cerebellar slices triggered a time-dependent increase of Bcl-2 and Bcl-xL expression. This SCT-induced transcriptional regulation of Bcl-2 and Bcl-xL was dependent on the cyclic AMP (cAMP) response element-binding protein (CREB), which is a key survival factor at the convergence of multiple signaling cascades. We further demonstrated that activation of CREB by SCT was mediated by cAMP/protein kinase A (PKA) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2 (ERK1/2) cascades. These findings, collectively, provide an uncharacterized signaling cascade for SCT-mediated neuronal survival, in which SCT promotes the key anti-apoptotic elements Bcl-2 and Bcl-xL in the intrinsic death pathway through PKA- and ERK-regulated CREB phosphorylation.

In vivo actions of SCTR/AT1aR heteromer in controlling Vp expression and release via cFos/cAMP/CREB pathway in magnocellular neurons of PVN.

With an increasing body of evidence regarding GPCR oligomerization and its clinical implications over the last decade, the modulation and dynamics of GPCR homo- and hetero-oligomers has more recently become an area of intense research focus. Previously, our lab showed in vitro heteromer formation between angiotensin II receptor type 1 subtype a (AT1aR) and secretin receptor (SCTR), which is involved in in vivo control of hyperosmolality-induced water drinking behavior. Because the secretin (SCT)/SCTR axis is crucial to the central actions of angiotensin II (ANGII) and both SCT and ANGII are capable of triggering vasopressin (Vp) release from hypothalamus, we investigated here the in vivo role of SCTR-AT1aR heteromer in regulating Vp release in hypothalamus using transmembrane peptides as tools. We showed that SCTR-AT1aR heteromer mediates stimulatory actions of both SCT and ANGII in hypothalamic Vp expression and release as well as neuronal activities via the immediate early gene cFos. The results from this study not only are consistent with our hypothesis that SCT and ANGII interact at the receptor level to mediate their water homeostatic activities but also provide evidence for in vivo functions of cross-class GPCR heteromers.-Mak, S. O. K., Zhang, L., Chow, B. K. C. In vivo actions of SCTR/AT1aR heteromer in controlling Vp expression and release via cFos/cAMP/CREB pathway in magnocellular neurons of PVN.

Distribution and Functional Implication of Secretin in Multiple Brain Regions.

Secretin is a polypeptide hormone initially identified for its gastrointestinal functions. However, emerging evidences show wide distribution of secretin and secretin receptor across various brain regions from cerebral cortex, hippocampus, hypothalamus to cerebellum. In this mini review, we will firstly describe the region-specific expression pattern of secretin and secretin receptor in the brain, followed by a summary of central physiological and neurological functions mediated by secretin. Using genetic manipulation and pharmaceutical approaches, one can elucidate the role of secretin in mediating various neurological functions from simple behaviors, such as water and food intake, to more complex functions including emotion, motor, and learning or memory. At last, current weakness and future perspectives of secretin in the central nervous system will be discussed, aiming to provide the potency of using secretin or its analog for treating various neurological disorders.

BDNF mimetic alleviates body weight gain in obese mice by enhancing mitochondrial biogenesis in skeletal muscle.

BACKGROUND: 7,8-Dihydroxyflavone (7,8-DHF) is a small molecular weight compound that mimics the functions of brain-derived neurotrophic factor (BDNF). The current study aims to elucidate the molecular mechanism of 7,8-DHF-induced body weight regulation. METHODS: Obese female C57/BL6 (20-week-old) mice that have been fed with high-fat diet for 13 weeks were treated with 7,8-DHF for 9 weeks. Various biochemical and molecular analyses were performed to examine the signal transduction pathway, metabolite content, and mitochondrial mass in the animals. Moreover, systemic energy metabolism and insulin sensitivity were determined by indirect calorimetry and insulin/glucose-tolerance tests. We have also determined the metabolic actions of 7,8-DHF on cultured myotubes. RESULTS: 7,8-DHF treatment increased cellular respiration by promoting mitochondrial biogenesis in cultured skeletal muscle cells. In diet-induced obese mice, subsequent 7,8-DHF consumption triggered the AMPK/CREB/PGC-1α pathways to increase the muscular mitochondrial content. Systemic energy metabolism was thus elevated, which reduced the body weight gain in obese animals. Consequently, hyperlipidemia, hyperglycemia hyperinsulinemia, and ectopic lipid accumulation in skeletal muscle and liver of the obese animals were alleviated after 7,8-DHF treatment. Moreover, insulin sensitivity of the obese muscle was improved after 7,8-DHF consumption. CONCLUSION: 7,8-DHF treatment increases muscular mitochondrial respiration and systemic energy expenditure, which alleviates the body weight gain and partially reverse the metabolic abnormalities induced by obesity.

Secretin Modulates the Postnatal Development of Mouse Cerebellar Cortex Via PKA- and ERK-dependent Pathways.

Postnatal development of the cerebellum is critical for its intact function such as motor coordination and has been implicated in the pathogenesis of psychiatric disorders. We previously reported that deprivation of secretin (SCT) from cerebellar Purkinje neurons impaired motor coordination and motor learning function, while leaving the potential role of SCT in cerebellar development to be determined. SCT and its receptor (SCTR) were constitutively expressed in the postnatal cerebellum in a temporal and cell-specific manner. Using a SCT knockout mouse model, we provided direct evidence showing altered developmental patterns of Purkinje cells (PCs) and granular cells (GCs). SCT deprivation reduced the PC density, impaired the PC dendritic formation, induced accelerated GC migration and potentiated cerebellar apoptosis. Furthermore, our results indicated the involvement of protein kinase A (PKA) and extracellular signal regulated kinase (ERK) signaling pathways in SCT-mediated protective effects against neuronal apoptosis. Results of this study illustrated a novel function of SCT in the postnatal development of cerebellum, emphasizing the necessary role of SCT in cerebellar-related functions.

Designing Dietary Recommendations Using System Level Interactomics Analysis and Network-Based Inference.

Background: A range of computational methods that rely on the analysis of genome-wide expression datasets have been developed and successfully used for drug repositioning. The success of these methods is based on the hypothesis that introducing a factor (in this case, a drug molecule) that could reverse the disease gene expression signature will lead to a therapeutic effect. However, it has also been shown that globally reversing the disease expression signature is not a prerequisite for drug activity. On the other hand, the basic idea of significant anti-correlation in expression profiles could have great value for establishing diet-disease associations and could provide new insights into the role of dietary interventions in disease. Methods: We performed an integrated analysis of publicly available gene expression profiles for foods, diseases and drugs, by calculating pairwise similarity scores for diet and disease gene expression signatures and characterizing their topological features in protein-protein interaction networks. Results: We identified 485 diet-disease pairs where diet could positively influence disease development and 472 pairs where specific diets should be avoided in a disease state. Multiple evidence suggests that orange, whey and coconut fat could be beneficial for psoriasis, lung adenocarcinoma and macular degeneration, respectively. On the other hand, fructose-rich diet should be restricted in patients with chronic intermittent hypoxia and ovarian cancer. Since humans normally do not consume foods in isolation, we also applied different algorithms to predict synergism; as a result, 58 food pairs were predicted. Interestingly, the diets identified as anti-correlated with diseases showed a topological proximity to the disease proteins similar to that of the corresponding drugs. Conclusions: In conclusion, we provide a computational framework for establishing diet-disease associations and additional information on the role of diet in disease development. Due to the complexity of analyzing the food composition and eating patterns of individuals our in silico analysis, using large-scale gene expression datasets and network-based topological features, may serve as a proof-of-concept in nutritional systems biology for identifying diet-disease relationships and subsequently designing dietary recommendations.