Jürg Gertsch

Universität Bern | UniBe · Institute of Biochemistry and Molecular Medicine

In eukaryotes, the C20:4 polyunsaturated fatty acid arachidonic acid (AA) plays important roles as a phospholipid component, signaling molecule and precursor of the endocannabinoid-prostanoid axis. Accordingly, the absence of AA causes detrimental effects. Here, compensatory mechanisms involved in AA deficiency in Caenorhabditis elegans were invest...

Hemopressins ((x)-PVNFKLLSH) or peptide endocannabinoids (pepcans) can bind to cannabinoid receptors. RVD-hemopressin (pepcan-12) was shown to act as endogenous allosteric modulator of cannabinoid receptors, with opposite effects on CB1 and CB2, respectively. Moreover, the N-terminally elongated pepcan-23 was detected in different tissues and was p...

Globally, more than six million people are infected with Trypanosoma cruzi, the causative protozoan parasite of the vector-borne Chagas disease. We conducted a cross-sectional ethnopharmacological field study in Bolivia among different ethnic groups where CD is hyperendemic. A total of 775 extracts of botanical drugs used in Bolivia in the context...

Amino acids are essential components of all living cells serving as building blocks of proteins, as energy source, and as precursors of metabolites and signaling molecules. Amino acid transporters are membrane proteins that mediate the transfer of amino acids across the plasma membrane, and between compartments in cells, different cells and organs....

Endocannabinoids at nanomolar physiological concentrations cross cellular membranes by facilitated diffusion, a process that can be studied by measuring transport kinetics and endocannabinoid trafficking employing radioligands and mass spectrometry. Here, we describe radiosubstrate-based assays using arachidonoyl[1-3H]ethanolamine and 2-arachidonoy...

A series of derivatives of the substrate amino acid Ltryptophan have been investigated for inhibition of the L‐type amino acid transporter LAT1 (SLC7A5), which is an emerging target in anticancer drug discovery. Of the four isomeric 4‐, 5‐, 6‐, or 7benzyloxy‐L‐tryptophans, the 5‐substituted derivative was the most potent, with an IC 50 of 19 μM for...

Monoacylglycerol lipase (MAGL) is the enzyme responsible for the metabolism of 2-arachidonoylglycerol in the brain and the hydrolysis of peripheral monoacylglycerols. Many studies demonstrated beneficial effects deriving from MAGL inhibition for neurodegenerative diseases, inflammatory pathologies, and cancer. MAGL expression is increased in invasi...

BACKGROUND AND AIMS Diabetic kidney disease (DKD), the renal manifestation of diabetes, contributes to increased morbidity and mortality of patients with diabetes. Activation of the cannabinoid-1 receptor (CB1R) and the mammalian target of rapamycin complex 1 (mTORC1) in the renal proximal tubular cells (RPTCs) contributes to the development of DKD...

Activation of the cannabinoid-1 receptor (CB1R) and the mammalian target of rapamycin complex 1 (mTORC1) in the renal proximal tubular cells (RPTCs) contributes to the development of diabetic kidney disease (DKD). However, the CB1R/mTORC1 signaling axis in the kidney has not been described yet. We show here that hyperglycemia-induced endocannabinoi...

Scoparone (6,7-dimethoxycoumarin) is a simple coumarin from botanical drugs of Artemisia species used in Traditional Chinese Medicine and Génépi liquor. However, its bioavailability to the brain and potential central effects remain unexplored. We profiled the neuropharmacological effects of scoparone upon acute and subchronic intraperitoneal admini...

LAT1 (SLC7A5) is one of the representative light chain proteins of heteromeric amino acid transporters, forming a heterodimer with its heavy chain partner 4F2hc (SLC3A2). LAT1 is overexpressed in many types of tumors and mediates the transfer of drugs and hormones across the blood-brain barrier. Thus, LAT1 is considered as a drug target for cancer...

Piper spices represent an inexhaustible reservoir of bioactive compounds that may act as drug leads in natural product research. The aim of this study was to investigate a series of meth-anolic fruit extracts obtained from P. nigrum (black, green, white and red), P. longum and P. retro-fractum in comparative phytochemical and multi-directional biol...

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targe...

The principle endocannabinoids are 2-acylglycerol esters, such as 2-arachidonoylglycerol (2-AG), and N-acylethanolamines, such as anandamide (N-arachidonoylethanolamine, AEA). The glycerol esters and ethanolamides are synthesised and hydrolysed by parallel, independent pathways. Mechanisms for release and re-uptake of endocannabinoids are unclear,...

The cis-stereoisomers of Δ⁹-THC [(−)-3 and (+)-3] were identified and quantified in a series of low-THC-containing varieties of Cannabis sativa registered in Europe as fiber hemp and in research accessions of cannabis. While Δ⁹-cis-THC (3) occurs in cannabis fiber hemp in the concentration range of (−)-Δ⁹-trans-THC [(−)-1], it was undetectable in a...

Endocannabinoid (eCB) levels fluctuate in inflammatory conditions and as such may take part in endometriosis-associated pain or even in endometriosis pathogenesis. In this case-control (23 cases and 19 controls) study, targeted lipids were measured in the serum and peritoneal fluid collected during laparoscopy. Endometriosis was confirmed histologi...

Agents targeting the endocannabinoid system (ECS) have gained attention as potential cancer treatments. Given recent evidence that cannabinoid receptor 2 (CB2R) regulates lymphocyte development and inflammation, we performed studies on CB2R in the immune response against melanoma. Analysis of The Cancer Genome Atlas (TCGA) data revealed a strong po...

The modulation of the endocannabinoid system (ECS) has shown positive results in animal models of multiple sclerosis (MS) and immune and inflammatory disorders. However, chronic administration of CB1 receptor agonists and degrading enzyme inhibitors can lead to CB1 receptor desensitization and sedation. WOBE437 is the prototype of a new class of EC...

The plant genus Piper comprises extensively consumed spice taxa like black pepper (P. nigrum L.) or long pepper (P. longum L.). The chronic dietary use of different Piper spices has been associated with different health benefits, though the molecular mechanisms remain poorly understood. The aim of this work was to perform the liquid-chromatography-...

An interesting enzyme of the endocannabinoid system is monoacylglycerol lipase (MAGL). This enzyme, which metabolizes the endocannabinoid 2-arachidonoylglycerol (2-AG), has attracted great interest due to its involvement in several physiological and pathological processes, such as cancer progression. Experimental evidences highlighted some drawback...

Multiple sclerosis is a chronic inflammatory demyelinating disorder of the central nervous system that eventually leads to progressive neurodegeneration and disability. Recent findings highlighted the emerging role of each target of the endocannabinoid system in controlling the symptoms and disease progression of multiple sclerosis. Therefore, mult...

The endocannabinoid system (ECS) comprises two major endocannabinoids (eCBs), 2-arachidonoyl glycerol (2-AG) and N-arachidonoylethanolamine (AEA), which act via the cannabinoid receptors CB1 and CB2. The ECS represents a major retrograde inhibitory system at chemical synapses and further modulates immune and metabolic processes related to stress. U...

We describe the convergent synthesis of three prototypical examples of a new class of analogs of the complex, cytotoxic marine macrolide (−)‐zampanolide, which incorporate an embedded N‐ substituted morpholine moiety in place of the natural tetrahydropyran ring. The final construction of the macrolactone core was based on a high‐yielding intramolec...

The placenta supplies the foetus with critical nutrients such as essential amino acids (AA, eg leucine) for development and growth. It also represents a cellular barrier which is formed by a polarized, differentiated syncytiotrophoblast (STB) monolayer. Active Na+-independent leucine transport across the placenta is mainly attributed to the System...

Cannabinoids are part of an endogenous signaling system found throughout the body, including the eye. Hepler and Frank showed in the early 1970s that plant cannabinoids can lower intraocular pressure (IOP), an effect since shown to occur via cannabinoid CB1 and GPR18 receptors. Endocannabinoids are synthesized and metabolized enzymatically. Enzymes...

Pharmacological modulation of cannabinoid type 2 receptor (CB2R) holds promise for the treatment of numerous con-ditions, including inflammatory diseases, autoimmune disorders, pain, and cancer. Despite the significance of this re-ceptor, researchers lack reliable tools to address questions concerning the expression and complex mechanism of CB2R si...

Genetic deletion of cannabinoid CB1 receptors or diacylglycerol lipase alpha (DAGLa), the main enzyme involved in the synthesis of the endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG), produced profound phenotypes in animal models of depression-related behaviors. Furthermore, clinical studies have shown that antagonists of CB1 can increase the i...

Pharmacological modulation of cannabinoid type 2 receptor (CB₂R) holds promise for the treatment of numerous conditions, including inflammatory diseases, autoimmune disorders, pain, and cancer. Despite the significance of this receptor, researchers lack reliable tools to address questions concerning the expression and complex mechanism o...

WOBE437 ((2 E ,4 E )‐N‐(3,4‐dimethoxyphenethyl)dodeca‐2,4‐dienamide, 1 ) is a natural product‐derived, highly potent inhibitor of endocannabinoid reuptake. In this study, we have synthesized almost 80 analogs of 1 with different types of modifications in the dodecadienoyl domain as well as the dimethoxyphenylethyl head group and we have investigate...

Psychoactive plants and plant natural products (NPs) were instrumental in early neuroscience research, and recreational or toxic NPs have played major roles in the discovery of virtually all neurotransmitter systems. Here, we review the contribution of NPs to psychosis, a heterogeneous neuropsychiatric condition characterized by conflicting percept...

Enhanced prostaglandin production promotes the development and progression of cancer. Prostaglandins are generated from arachidonic acid (AA) by the action of cyclooxygenase (COX) isoenzymes. However, how cancer cells are able to maintain an elevated supply of AA for prostaglandin production remains unclear. Here, by using lung cancer cell lines an...

Astrocytes orchestrate neural development by powerfully coordinating synapse formation and function and, as such, may be critically involved in the pathogenesis of neurodevelopmental abnormalities and cognitive deficits commonly observed in psychiatric disorders. Here, we report the identification of a subset of cortical astrocytes that are compete...

Globally, more than six million people are infected with Trypanosoma cruzi , the causative protozoan parasite of the vector-borne Chagas disease (CD). In Bolivia, CD is hyperendemic and a major health problem among indigenous communities. Although botanical drugs are used widely among different ethnic groups in Bolivia, studies challenging the hypo...

Pharmacological modulation of cannabinoid type 2 receptor (CB2R) holds promise for the treatment of numerous conditions including inflammatory diseases, autoimmune disorders, pain, and cancer. Despite its significance, researchers lack reliable tools to address questions concerning the complex mechanism of CB2R signaling and its downstream conseque...

Cannabinoid type 2 receptor (CB₂R) is a fundamental part of the endocannabinoid signaling system (eCB system), and is known to play an important role in tissue injury, inflammation, cancer and pain. In stark contrast to its significance, the underlying signaling mechanisms and tissue expression profiles are poorly understood. Due to its...

Cannabinoid type 2 receptor (CB 2 R) is a fundamental part of the endocannabinoid signaling system (eCB system), and is known to play an important role in tissue injury, inflammation, cancer and pain. In stark contrast to its significance, the underlying signaling mechanisms and tissue expression profiles are poorly understood. Due to its low expre...

Pharmacological modulation of cannabinoid type 2 receptor (CB2R) holds promise for the treatment of numerous conditions including inflammatory diseases, autoimmune disorders, pain, and cancer. Despite its significance, researchers lack reliable tools to address questions concerning the complex mechanism of CB2R signaling and its downstream conseque...

Several preclinical evidence indicate that the modulation of the endocannabinoid system (ECS) represents a promising therapeutic approach for different diseases. However, only few modulators of this system have reached so far an advanced stage of clinical development, mainly due to limited efficacy and CB1 receptor-dependent side effects. Those lim...

The principle endocannabinoids are 2-acylglycerol esters, such as 2-arachidonoylglycerol (2-AG), and N-acylethanolamines, such as anandamide (N-arachidonoylethanolamine, AEA). The glycerol esters and ethanolamides are synthesised and hydrolysed by parallel, independent pathways. Mechanisms for release and re-uptake of endocannabinoids are unclear,...

The Front Cover shows Guineensine in the foreground, a natural product derived from the fruits of black pepper, Piper nigrum, and several other pepper species. Guineensine is a natural uptake inhibitor of endocannabinoids, thereby showing cannabimimetic and also pronounced antiinflammatory effects. The authors devised a total synthesis of Guineensi...

Guineensine ((2E,4E,12E)‐13‐(benzo[d][1,3]dioxol‐5‐yl)‐N‐isobutyltrideca‐2,4,12‐trienamide) is a plant‐derived natural product that inhibits the reuptake of the endocannabinoid anandamide with sub‐μM potency. We have established a highly efficient total synthesis of guineensine, which provided the natural product in only 5 steps from commercially a...

Background: Chagas disease remains a major public health risk in Bolivia, particularly among rural indigenous communities. Here we studied the cultural perception of the triatomine vectors and Chagas disease among selected rural and urban ethnic groups from different socio-economic and geographical milieus. We focused on the indigenous communities...

Radula marginata Taylor is a subtropical liverwort, endemic to the Northern island of New Zealand in the Pacific region. Despite its significant potential as an alternative source of a THC-like phytocannabinoid, the biosynthesis of this compound remains elusive. Following the discovery of a bibenzyl cis-tetrahydrocannabinol (perrottetinene) in R. m...

Background: Cancer-associated bone disease is a serious complication in bone sarcomas and metastatic carcinomas of breast and prostate origin. Monoacylglycerol lipase (MAGL) is an enzyme of the endocannabinoid system, and is responsible for the degradation of the most abundant endocannabinoid in bone, 2-arachidonoyl glycerol (2AG). Methods: The ef...

Purpose The aim of the present study was to evaluate the cytotoxicity of five synthetic cannabinoids in two cell lines, for which both reference standards and herbal blends were available. Methods An in-house smoking device was developed to produce smoke condensates. The cell viability of reference standards, herbal blend extracts and smoke conden...

A series of new 3‐deoxy‐C12,C13‐trans‐cyclopropyl‐epothilones have been prepared, bearing benzothiazole, quinoline, thiazol‐5‐ylvinyl, or isoxazol‐3‐ylvinyl side chains. For analogs with fused aromatic side chains, macrocyclic ring‐closure was based on ring‐closing olefin metathesis (RCM) of a precursor incorporating the fully elaborated heavy atom...

Chemical probes that irreversibly inhibit protein function may be used across species to discover proteins. Combining phenotypic screening and activity-based protein profiling, a new study uncovers a discrete lipid signaling pathway regulating lifespan in the worm Caenorhabditis elegans.

We recently reported 4-chloro-2-(2-chlorophenoxy)acetamido)benzoic acid (CBA) as the first potent inhibitor of TRPM4, a cation channel implicated in cardiac diseases and prostate cancer. Herein we report a structure-activity relationship (SAR) study of CBA resulting in two new potent analogs. To design and interpret our SAR we used interactive colo...

Monoacylglycerol lipase (MAGL) is the enzyme degrading the endocannabinoid 2-arachidonoylglycerol and it is involved in several physiological and pathological processes. The therapeutic potential of MAGL is linked to several diseases, including cancer. The development of MAGL inhibitors has been greatly limited by the side effects associated with t...

Performance and conflict monitoring (PM and CM) represent two essential cognitive abilities, required to respond appropriately to demanding tasks. PM and CM can be investigated using event-related brain potentials (ERP) and associated neural oscillations. Namely, the error-related negativity (ERN) represents a correlate of PM, whereas the N2 compon...

Background: The L-type amino acid transporter 1 (LAT1/SLC7A5) transports essential amino acids across the plasma membrane. While LAT1 is overexpressed in a variety of human neoplasms, its expression and its role in thyroid cancer is currently unknown. Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy for which no effective thera...

A series of 1-trifluoromethyl substituted indanes and indenes bearing aryl groups in positions 1 and/or 3 of the indane core have been synthesized mainly by electrophilic cyclization and arylation of the corresponding trifluoromethylated allyl and propargyl alcohols. The distinctly lipophilic compounds thus obtained were tested against various comp...

Phytochemical studies on the liverwort Radula genus have previously identified the bibenzyl (−)- cis -perrottetinene ( cis -PET), which structurally resembles (−)-Δ ⁹ - trans -tetrahydrocannabinol (Δ ⁹ - trans -THC) from Cannabis sativa L. Radula preparations are sold as cannabinoid-like legal high on the internet, even though pharmacological data...

The botanical drug cannabis flos (inflorescence of Cannabis sativa L.) has a unique popular status as being a potent recreational drug and bona fide universal remedy (panacea). Generally, cannabinoids exert therapeutic effects in a broad range of pathophysiologies related to inflammation, pain, metabolic and stress-related conditions in preclinical...

Figure S1 TRPM4 currents in excised membrane patches: Representative current traces from excised membrane patches when exposed to either 0 (black) or 500 μM Ca2+ (blue) from TRPM4 expressing cells either induced with tetracycline or non‐induced and TRPM4 CRISPR‐Cas9 knocked down cell line (KD). Steady state IVs was constructed from currents at the...

Table S5 Analytical RP‐UPLC purity. a) The spectra were obtained according to method B (see description in general remarks). b) A partial decomposition of the compound was observed preventing any purity analysis. c) Any UPLC trace could be obtained due to either too few material or precipitation in UPLC solvents. NMR purity was considered (>90%).

Different anandamide (AEA) transport inhibitors show antinociceptive and antiinflammatory effects in vivo, but due to their concomitant inhibition of fatty acid amide hydrolase (FAAH) and overall poor bioavailability, they cannot be used unequivocally to study the particular role of endocannabinoid (EC) transport in pathophysiological conditions in...

The endocannabinoid system (ECS) represents one of the major neuromodulatory systems involved in different physiological and pathological processes. Multi-target compounds exert their activities by acting via multiple mechanisms of action and represent a promising pharmacological modulation of the ECS. In this work we report 4-substituted and 4,5-d...

Background and purpose: TRPM4 is a calcium-activated nonselective cation channel expressed in many tissues and implicated in several diseases, and has not yet been validated as a therapeutic target due to the lack of potent and selective inhibitors. We sought to discover a novel series of small-molecule inhibitor by combining in silico methods and...

From acetonic extract of the whole plant Euphorbia pterococca Brot. (Euphorbiaceae), four new cycloartane-type ester triterpenes named cycloartenyl-2'E,4'E-decadienoate (1), cycloartenyl-2'E,4'Z-decadienoate (2), 24-methylenecycloartanyl-2'E,4'Z-tetradecadienoate (3), and 24-oxo-29-norcycloartanyl-2'E,4'Z-hexadecadienoate (4) were obtained along wi...

We have previously shown that i) endocannabinoids (eCB; e.g. anandamide [AEA]) are involved in the maintenance of homeostatic sebaceous lipid production (SLP) in human sebaceous glands (SG); and ii) eCB treatment dramatically increases SLP. Here, we aimed to investigate the expression of the major eCB synthesizing and degrading enzymes, and to stud...

Monoacylglycerol lipase (MAGL) is a serine hydrolase that plays an important role in the degradation of the endocannabinoid neurotransmitter 2-arachidonoylglycerol, which is implicated in many physiological processes. Beyond the possible utilization of MAGL inhibitors as anti-inflammatory, anti-nociceptive and anti-cancer agents, their application...