Papers by Johannes Grosse
Background: Gastrointestinal (GI) disorders are commonly associated with chronic conditions such ... more Background: Gastrointestinal (GI) disorders are commonly associated with chronic conditions such as diabetes, obesity, and hypertension. Direct consequences are obstipation or diarrhea as opposite aspects of the irritable bowel syndrome, and more indirectly, alteration of appetite, feeling of fullness, flatulence, bloatedness, and eventually leading to altered absorption of nutrients. Moreover, GI retention and passage times have been recognized as important factors in determining the release site and hence the bioavailability of orally administered drugs. To facilitate the understanding of physiological and pathological processes involved, it is necessary to monitor the gut motility in animal models. Here, we describe a method for studying the GI transit time using technetium-labeled activated charcoal diethylenetriaminepentaacetic acid (99mTc-Ch-DTPA) detected by single-photon emission computed tomography (SPECT). Methods: Tc-DTPA was adsorbed onto activated charcoal and administe...
The SMA1-mouse is a novel ethyl-nitroso-urea (ENU)-induced mouse mutant that carries an a3g misse... more The SMA1-mouse is a novel ethyl-nitroso-urea (ENU)-induced mouse mutant that carries an a3g missense mutation in exon 5 of the GH gene, which translates to a D167G amino acid exchange in the mature protein. Mice carrying the mutation are characterized by dwarfism, predominantly due to the reduction (sma1/�) or absence (sma1/sma1) of the GH-mediated peripubertal growth spurt, with sma1/ � mice displaying a less pronounced phenotype. All genotypes are viable and fertile, and the mode of inheritance is in accordance with a semidominant Mendelian trait. Adult SMA1 mice accumulate excessive amounts of sc and visceral fat in the presence of GH, A 22-kDa PROTEIN hormone of 191 (human) or 190 (mouse) amino acids synthesized and released from the acidophil cells of the anterior pituitary gland, possesses well-documented anabolic as well as lipolytic activity (1). In
L'invention concerne des polypeptides du recepteur couple aux proteines G (GPCR) GPR146 compr... more L'invention concerne des polypeptides du recepteur couple aux proteines G (GPCR) GPR146 comprenant la sequence d'acides amines indiquee dans la SEQ ID n° 3 ou la SEQ ID n° 5 et des homologues, des variantes et des derives de ceux-ci. L'invention concerne egalement des acides nucleiques capables de coder pour le polypeptide du GPR146, en particulier ceux comprenant les sequences d'acide nucleique indiquees dans la SEQ ID n° 1A, la SEQ ID n° 1B, la SEQ ID n° 2 ou la SEQ ID n° 4. Le recepteur GPR146 est utile dans le diagnostic et la therapie de dyslipidemies.
Genes, 2020
Drug development (target identification, advancing drug leads to candidates for preclinical and c... more Drug development (target identification, advancing drug leads to candidates for preclinical and clinical studies) can be facilitated by genetic and genomic knowledge. Here, we review the contribution of population genomics to target identification, the value of bulk and single cell gene expression analysis for understanding the biological relevance of a drug target, and genome-wide CRISPR editing for the prioritization of drug targets. In genomics, we discuss the different scope of genome-wide association studies using genotyping arrays, versus exome and whole genome sequencing. In transcriptomics, we discuss the information from drug perturbation and the selection of biomarkers. For CRISPR screens, we discuss target discovery, mechanism of action and the concept of gene to drug mapping. Harnessing genetic support increases the probability of drug developability and approval.
Neurochemical Research, 2019
akan menyebabkan terjadinya sepsis dengan adanya pelepasan sitokin proinflamasi seperti TNF-á, IL... more akan menyebabkan terjadinya sepsis dengan adanya pelepasan sitokin proinflamasi seperti TNF-á, IL-1â, IL-8 berhubungan dengan kerusakan endotel dan jaringan. Ketamin mensupresi produksi LPS-induced TNF-, IL-6 dan dan rhTNF-induced IL-6 and IL-8 dalam darah manusia. Tujuan. Mengetahui pengaruh pemberian ketamin terhadap jumlah sel makrofag ginjal dan pengaruh perbedaan waktu dan cara pemberian pemberian ketamin terhadap sel makrofag tikus. Metode. Penelitian menggunakan metode experimental, dengan sampel hewan coba tikus putih rattus norvegicus dari galur wistar model sepsis menggunakan metode fecal induced peritonitis (FIP). Sampel dibagi menjadi enam kelompok perlakuan yaitu : kontrol negatif (-), kontrol positif (+), pemberian ketamin 5mg/ kgbb pada jam ke-0 (A), ke-3 (B), ke-5 (C) dan pemberian berturut-turut pada jam ke 0,2,4 (D). Analisa data menggunakan anova dan post hoc test. Hasil. Analisis anova diperoleh nilai signifikansi sebesar 0,000 (p<0,05) yang menunjukkan ada perbedaan bermakna rerata antar tiap kelompok perlakuan. Hasil uji post hoc test didapat nilai signifikansi yang berbeda yang menunjukkan waktu pemberian ketamin berpengaruh positif terhadap jumlah makrofag ginjal tikus model sepsis. Kesimpulan. Waktu dan cara pemberian ketamin berpengaruh positif terhadap jumlah makrofag ginjal tikus serta terdapat perbedaan jumlah makrofag pada setiap kelompok perlakuan pemberian ketamin.
Scientific reports, Jan 26, 2016
Knockout mice studies implicate the mammalian short-chain fatty acid (SCFA) receptors, FFAR2 and ... more Knockout mice studies implicate the mammalian short-chain fatty acid (SCFA) receptors, FFAR2 and FFAR3- in colitis, arthritis and asthma. However, the correlation with human biology is uncertain. Here, we detected FFAR2 and FFAR3 expression in human monocytes via immunohistochemistry. Upon treatment with acetate SCFA or FFAR2- and FFAR3-specific synthetic agonists, human monocytes displayed elevated p38 phosphorylation and attenuated C5, CCL1, CCL2, GM-CSF, IL-1α, IL-1β and ICAM-1 inflammatory cytokine expression. Acetate and FFAR2 agonist treatment also repressed Akt and ERK2 signalling. Surprisingly, mouse monocytes displayed a distinct response to acetate treatment, elevating GM-CSF, IL-1α, and IL-1β cytokine expression. This effect persisted in FFAR2/3-knockout mouse monocytes and was not reproduced by synthetic agonists, suggesting a FFAR2/3 independent mechanism in mice. Collectively, we show that SCFAs act via FFAR2/3 to modulate human monocyte inflammatory responses- a pathw...
Journal of Medicinal Chemistry, 2016
Insulin-like peptide 5 (INSL5) has recently been discovered as only the second orexigenic gut hor... more Insulin-like peptide 5 (INSL5) has recently been discovered as only the second orexigenic gut hormone after ghrelin. As we have previously reported, INSL5 is extremely difficult to assemble and oxidize into its two-chain three-disulfide structure. The focus of this study was to generate structure-activity relationships (SAR) of INSL5 and use it to develop a potent and simpler INSL5 mimetic with RXFP4 agonist activity. A series of human and mouse INSL5 (hINSL5/mINSL5) analogues were designed and chemically synthesized, resulting in a chimeric INSL5 analogue exhibiting more than 10-fold higher potency (0.35 nM) at human RXFP4 compared with native hINSL5 (4.57 nM). The SAR study also identified a key residue (KA15) in the A-chain of mINSL5 that contributes to improved RXFP4 affinity and potency of mINSL5 compared with hINSL5. This knowledge ultimately led us to engineer a minimized hINSL5 mimetic agonist that retains native hINSL5-like RXFP4 affinity and potency at human RXFP4. This minimized analogue was synthesized in 17.5 fold higher yield and in less time compared with hINSL5.
Amino acids, Jan 11, 2015
Insulin-like peptide 5 (INSL5) is an orexigenic peptide hormone belonging to the relaxin family o... more Insulin-like peptide 5 (INSL5) is an orexigenic peptide hormone belonging to the relaxin family of peptides. It is expressed primarily in the L-cells of the colon and has a postulated key role in regulating food intake. Its G protein-coupled receptor, RXFP4, is a potential drug target for treating obesity and anorexia. We studied the effect of modification of the C-terminus of the A and B-chains of human INSL5 on RXFP4 binding and activation. Three variants of human INSL5 were prepared using solid phase peptide synthesis and subsequent sequential regioselective disulfide bond formation. The peptides were synthesized as C-terminal acids (both A- and B-chains with free C-termini, i.e., the native form), amides (both chains as the C-terminal amide) and one analog with the C-terminus of its A-chain as the amide and the C-terminus of the B-chain as the acid. The results showed that C-terminus of the B-chain is more important than that of the A-chain for RXFP4 binding and activity. Amidat...
Diabetes, 2015
Free fatty acid receptor 2 (FFA2) is expressed on enteroendocrine L cells that release glucagon-l... more Free fatty acid receptor 2 (FFA2) is expressed on enteroendocrine L cells that release glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) when activated by short-chain fatty acids (SCFAs). Functionally GLP-1 and PYY inhibit gut transit, increase glucose tolerance, and suppress appetite; thus, FFA2 has therapeutic potential for type 2 diabetes and obesity. However, FFA2-selective agonists have not been characterized in vivo. Compound 1 (Cpd 1), a potent FFA2 agonist, was tested for its activity on the following: GLP-1 release, modulation of intestinal mucosal ion transport and transit in wild-type (WT) and FFA2−/− tissue, and food intake and glucose tolerance in lean and diet-induced obese (DIO) mice. Cpd 1 stimulated GLP-1 secretion in vivo, but this effect was only detected with dipeptidyl peptidase IV inhibition, while mucosal responses were PYY, not GLP-1, mediated. Gut transit was faster in FFA2−/− mice, while Cpd 1 slowed WT transit and reduced food intake and body weight in ...
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Papers by Johannes Grosse