Small synthetic molecules called growth hormone secretagogues (GHSs) stimulate the release of growth hormone (GH) from the pituitary. They act through the GHS-R, a G protein-coupled receptor whose ligand has only been discovered recently. Using a reverse pharmacology paradigm with a stable cell line expressing GHS-R, we purified an endogenous ligand for GHS-R from rat stomach and named it "ghrelin," after a word root ("ghre") in Proto-Indo-European languages meaning "grow." Ghrelin is a peptide hormone in which the third amino acid, usually a serine but in some species a threonine, is modified by a fatty acid; this modification is essential for ghrelin's activity. The discovery of ghrelin indicates that the release of GH from the pituitary might be regulated not only by hypothalamic GH-releasing hormone, but also by ghrelin derived from the stomach. In addition, ghrelin stimulates appetite by acting on the hypothalamic arcuate nucleus, a region known to control food intake. Ghrelin is orexigenic; it is secreted from the stomach and circulates in the bloodstream under fasting conditions, indicating that it transmits a hunger signal from the periphery to the central nervous system. Taking into account all these activities, ghrelin plays important roles for maintaining GH release and energy homeostasis in vertebrates.

https://www.physiology.org/doi/pdf/10.1152/physrev.00012.2004

Ghrelin: Structure and Function

The calpain system originally comprised three molecules: two Ca2+-dependent proteases, mu-calpain and m-calpain, and a third polypeptide, calpastatin, whose only known function is to inhibit the two calpains. Both mu- and m-calpain are heterodimers containing an identical 28-kDa subunit and an 80-kDa subunit that shares 55-65% sequence homology between the two proteases. The crystallographic structure of m-calpain reveals six "domains" in the 80-kDa subunit: 1). a 19-amino acid NH2-terminal sequence; 2). and 3). two domains that constitute the active site, IIa and IIb; 4). domain III; 5). an 18-amino acid extended sequence linking domain III to domain IV; and 6). domain IV, which resembles the penta EF-hand family of polypeptides. The single calpastatin gene can produce eight or more calpastatin polypeptides ranging from 17 to 85 kDa by use of different promoters and alternative splicing events. The physiological significance of these different calpastatins is unclear, although all bind to three different places on the calpain molecule; binding to at least two of the sites is Ca2+ dependent. Since 1989, cDNA cloning has identified 12 additional mRNAs in mammals that encode polypeptides homologous to domains IIa and IIb of the 80-kDa subunit of mu- and m-calpain, and calpain-like mRNAs have been identified in other organisms. The molecules encoded by these mRNAs have not been isolated, so little is known about their properties. How calpain activity is regulated in cells is still unclear, but the calpains ostensibly participate in a variety of cellular processes including remodeling of cytoskeletal/membrane attachments, different signal transduction pathways, and apoptosis. Deregulated calpain activity following loss of Ca2+ homeostasis results in tissue damage in response to events such as myocardial infarcts, stroke, and brain trauma.

The Calpain System

http://www.back-in-business-physiotherapy.com/images/files/DescendingControl.pdf

Descending control of pain.

Context Epidemiological studies have indicated an inverse association between cardiorespiratory fitness (CRF) and coronary heart disease (CHD) or all-cause mortality in healthy participants. Objective To define quantitative relationships between CRF and CHD events, cardiovascular disease (CVD) events, or all-cause mortality in healthy men and women. Data Sources and Study Selection A systematic literature search was conducted for observational cohort studies using MEDLINE (1966 to December 31, 2008) and EMBASE (1980 to December 31, 2008). The Medical Subject Headings search terms used included exercise tolerance, exercise test, exercise/physiology, physical fitness, oxygen consumption, cardiovascular diseases, myocardial ischemia, mortality, mortalities, death, fatality, fatal, incidence, or morbidity. Studies reporting associations of baseline CRF with CHD events, CVD events, or all-cause mortality in healthy participants were included. Data Extraction Two authors independently extracted relevant data. CRF was estimated as maximal aerobic capacity (MAC) expressed in metabolic equivalent (MET) units. Participants were categorized as low CRF ( Data Synthesis Data were obtained from 33 eligible studies (all-cause mortality, 102 980 participants and 6910 cases; CHD/CVD, 84 323 participants and 4485 cases). Pooled RRs of all-cause mortality and CHD/CVD events per 1-MET higher level of MAC (corresponding to 1-km/h higher running/jogging speed) were 0.87 (95% confidence interval [CI], 0.84-0.90) and 0.85 (95% CI, 0.82-0.88), respectively. Compared with participants with high CRF, those with low CRF had an RR for all-cause mortality of 1.70 (95% CI, 1.51-1.92; P  Conclusions Better CRF was associated with lower risk of all-cause mortality and CHD/CVD. Participants with a MAC of 7.9 METs or more had substantially lower rates of all-cause mortality and CHD/CVD events compared with those with a MAC of less 7.9 METs.

https://jamanetwork.com/journals/jama/articlepdf/1108396/jcr90003_2024_2035.pdf

Cardiorespiratory Fitness as a Quantitative Predictor of All-Cause Mortality and Cardiovascular Events in Healthy Men and Women: A Meta-analysis

Background Puberty, a complex biologic process involving sexual development, accelerated linear growth, and adrenal maturation, is initiated when gonadotropin-releasing hormone begins to be secreted by the hypothalamus. We conducted studies in humans and mice to identify the genetic factors that determine the onset of puberty. Methods We used complementary genetic approaches in humans and in mice. A consanguineous family with members who lacked pubertal development (idiopathic hypogonadotropic hypogonadism) was examined for mutations in a candidate gene, GPR54, which encodes a G protein–coupled receptor. Functional differences between wild-type and mutant GPR54 were examined in vitro. In parallel, a Gpr54-deficient mouse model was created and phenotyped. Responsiveness to exogenous gonadotropin-releasing hormone was assessed in both the humans and the mice. Results Affected patients in the index pedigree were homozygous for an L148S mutation in GPR54, and an unrelated proband with idiopathic hypogonadotro...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa035322

The GPR54 gene as a regulator of puberty

Background: The dysfunction of protein degradation through the ubiquitin-proteasome system is now widely accepted as one of the causes of Alzheimer’s disease (AD)

Neuronal expression of F-box and leucine-rich-repeat protein 2 decreases over Braak stages in the brains of Alzheimer's disease patients.

Novel liver function controlling agents which contain proteins containing amino acid sequences which are the same or substantially the same as the amino acid sequences represented by SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3 or SEQ ID NO:31. These liver function controlling agents are useful as preventives/remedies for diseases such as liver insufficiency, hepatitis, liver cancer or liver cirrhosis.

Liver function controlling agents

An enhanced urethral closure reflex via the spinal cord is related to urethral resistance elevation during increased abdominal pressure. However, with the exception of monoamines, neurotransmitters modulating this reflex are not understood. We investigated whether the vasopressin V(₁A) receptor (V(₁A)R) is involved in the urethral closure reflex in urethane-anesthetized female rats. V(₁A)R mRNA was highly expressed among the vasopressin receptor family in the total RNA purified from lamina IX in the spinal cord L6-S1 segment. In situ hybridization analysis of the spinal L6-S1 segment confirmed that these positive signals from the V(₁A)Rs were only detected in lamina IX. Intrathecally injected Arg⁸-vasopressin (AVP), an endogenous ligand, significantly increased urethral resistance during an intravesical pressure rise, and its effect was blocked by the V(₁A)R antagonist. AVP did not increase urethral resistance in rats in which the pelvic nerves were transected bilaterally. Urethral closure reflex responses to the intravesical pressure rise increased by up to threefold compared with the baseline response after AVP administration in contrast to no increase by vehicle. In addition, intravenously and intrathecally injected V(₁A)R antagonists decreased urethral resistance. These results suggest that V(₁A)R stimulation in the spinal cord enhances the urethral closure reflex response, thereby increasing urethral resistance during an abdominal pressure rise and that V(₁A)R plays a physiological role in preventing urine leakage.

Role of vasopressin V1A receptor in the urethral closure reflex in rats

The present invention relates to a screening method for a compound or a salt thereof that alters the binding property of MCH or a salt thereof to SLT or a salt thereof, or a partial peptide thereof, an amide or an ester thereof, or a salt thereof, characterized by using MCH, a derivative or a salt thereof and SLT or a salt thereof, or a partial peptide thereof, an amide or an ester thereof, or a salt thereof. The screening method of the present invention is useful for screening an SLT agonist, which can be used as an agent for promoting appetite (eating), and an SLT antagonist, which can be used as a prophylactic and/or therapeutic agent for obesity.

Method for screening mch receptor antagonist/agonist

Highly purified recombiaant basic fibroblast growth factor (rbFGF) and acidic FGF (aFGF) stimulated the proliferation of human-human (h-h) hybridomas to the extent of over four-fold from a low cell density such as 1×103 cells per ml in a serum-free medium in 24-well plates. The stimulatory effect of rbFGF was also observed in various lymphoid cell lines. Expecting that FGF could be an autocrine growth factor, we introduced bFGF gene into a h-h hybridoma using an expression plasmid induced by dexamethasone. The transformed cells thus obtained, HPO-75.11bbFGF-7, were able to grow well from a low inoculum density in a serum-free medium and antibody production was also increased when bFGF gene expression was induced. The transformed cells could grow at clonal density in a serum-free medium in 96-well plates, though the original cells could not. We also obtained a more practical transfectant, HPO-75.29-H74, using a high-shear stress adapted clone as the recipient and an expression plasmid having bFGF gene under the control of metallothioneine-I promoter. The HOP-75.29-H74 cells were capable of growing and producing human monoclonal antibody against hepatitis B virus surface antigen from an inoculum density of 1×103 cells per ml in an agitation vessel without addition of an inducer.

Yasushi Shintani

Papers

Neuronal expression of F-box and leucine-rich-repeat protein 2 decreases over Braak stages in the brains of Alzheimer's disease patients.

Liver function controlling agents

Role of vasopressin V1A receptor in the urethral closure reflex in rats

Method for screening mch receptor antagonist/agonist

Improvement in the proliferative activity of human-human hybridomas at low cell density by transfection with bFGF gene.