Pharmacology of metformin - An update.

Despite being a successful diabetes type 2 drug for more than a half-century in Europe, the mode of action of metformin is still debated. It is the purpose of this review to inform the reader about most recent findings for metformin with respect to its antidiabetic activity as well as proposed benefits beyond glucose control in humans. Clinical evidence now suggests that most of metformin benefits originate from its actions in the gut, involving hormone signaling by glucagon-like peptide 1 and peptide YY.

Metformin and Aging: A Review.

Metformin is sometimes proposed to be an "anti-aging" drug, based on preclinical experiments with lower-order organisms and numerous retrospective data on beneficial health outcomes for type 2 diabetics. Large prospective, placebo-controlled trials are planned, in pilot stage or running, to find a new use (or indication) for an aging population. As one of the metformin trials has "frailty" as its endpoint, similar to a trial with a plant-derived senolytic, the latter class of novel anti-aging drugs is briefly discussed.

Torpor: The Rise and Fall of 3-Monoiodothyronamine from Brain to Gut-From Gut to Brain?

(T1AM), first isolated from rat brain, is reported to be an endogenous, rapidly acting metabolite of thyroxine. One of its numerous effects is the induction of a "torpor-like" state in experimental animals. A critical analysis of T1AM, to serve as an endogenous cryogen, is given.

Prospective virtual screening in a sparse data scenario: design of small-molecule TLR2 antagonists.

Toll-like receptors (TLRs) are critical signaling molecules with roles in various severe clinical conditions such as sepsis and rheumatoid arthritis, and have therefore been advocated as promising drug targets for the treatment of these diseases. The aim of this study was to discover small-molecule antagonists of TLR2 by computer-aided drug design. This goal poses several challenges due to the lack of available data on TLR2 modulators.

A marriage of two "Methusalem" drugs for the treatment of psoriasis?: Arguments for a pilot trial with metformin as add-on for methotrexate.

In this article we present arguments that the "antidiabetic" drug metformin could be useful as an add-on therapy to methotrexate for the treatment of psoriasis and, perhaps, for rheumatoid arthritis as well. Biochemical data suggest that both drugs may share a common cellular target, the AMP-activated protein kinase (AMPK). This enzyme is a master regulator of metabolism and controls a number of downstream targets, e.

Targeting the Kv1.3 potassium channel for immunosuppression in vascularized composite allotransplantation - a pilot study.

Kv1.3-channels are critically involved in activation and function of effector memory T cells. Blocking Kv1.

Does rosuvastatin increase serum levels of 25-hydroxy-vitamin D?

An observational study and a "clinical trial" seem to prove that rosuvastatin (but not fluvastatin) dramatically increases serum levels of 25-(OH)-D3 (three-fold above starting values). A critical analysis of the two publications, presented below, raises serious concerns. Conclusions from these two studies have already been drawn in the scientific literature.

Novel pharmacological chaperones that correct phenylketonuria in mice.

Phenylketonuria (PKU) is caused by inherited phenylalanine-hydroxylase (PAH) deficiency and, in many genotypes, it is associated with protein misfolding. The natural cofactor of PAH, tetrahydrobiopterin (BH(4)), can act as a pharmacological chaperone (PC) that rescues enzyme function. However, BH(4) shows limited efficacy in some PKU genotypes and its chemical synthesis is very costly.

Vitamin D, UV, and skin cancer in the elderly: to expose or not to expose?

There is mounting concern about vitamin D insufficiency, especially in the ageing population. Increases in indoor lifestyle, obesity, car travel, clothing habits, the use of photo-protective makeup, and campaigns driven by dermatologists, governments, and the cosmetic industry to avoid or protect against the sun as much as possible are contributing to this trend. In a recent article in Gerontology, Barysch et al.

Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling.

Hyperphosphorylated tau plays an important role in the formation of neurofibrillary tangles in brains of patients with Alzheimer's disease (AD) and related tauopathies and is a crucial factor in the pathogenesis of these disorders. Though diverse kinases have been implicated in tau phosphorylation, protein phosphatase 2A (PP2A) seems to be the major tau phosphatase. Using murine primary neurons from wild-type and human tau transgenic mice, we show that the antidiabetic drug metformin induces PP2A activity and reduces tau phosphorylation at PP2A-dependent epitopes in vitro and in vivo.

New insights into tetrahydrobiopterin pharmacodynamics from Pah enu1/2, a mouse model for compound heterozygous tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency.

Phenylketonuria (PKU), an autosomal recessive disease with phenylalanine hydroxylase (PAH) deficiency, was recently shown to be a protein misfolding disease with loss-of-function. It can be treated by oral application of the natural PAH cofactor tetrahydrobiopterin (BH(4)) that acts as a pharmacological chaperone and rescues enzyme function in vivo. Here we identified Pah(enu1/2) bearing a mild and a severe mutation (V106A/F363S) as a new mouse model for compound heterozygous mild PKU.

Pahenu1 is a mouse model for tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency and promotes analysis of the pharmacological chaperone mechanism in vivo.

The recent approval of sapropterin dihydrochloride, the synthetic form of 6[R]-l-erythro-5,6,7,8-tetrahydrobiopterin (BH(4)), for the treatment of phenylketonuria (PKU) as the first pharmacological chaperone drug initiated a paradigm change in the treatment of monogenetic diseases. Symptomatic treatment is now replaced by a causal pharmacological therapy correcting misfolding of the defective phenylalanine hydroxylase (PAH) in numerous patients. Here, we disclose BH(4) responsiveness in Pah(enu1), a mouse model for PAH deficiency.

Discovery of high-affinity ligands of sigma1 receptor, ERG2, and emopamil binding protein by pharmacophore modeling and virtual screening.

ERG2, emopamil binding protein (EBP), and sigma-1 receptor (sigma(1)) are enzymes of sterol metabolism and an enzyme-related protein, respectively, that share high affinity for various structurally diverse compounds. To discover novel high-affinity ligands, pharmacophore models were built with Catalyst based upon a series of 23 structurally diverse chemicals exhibiting K(i) values from 10 pM to 100 microM for all three proteins. In virtual screening experiments, we retrieved drugs that were previously reported to bind to one or several of these proteins and also tested 11 new hits experimentally, of which three, among them raloxifene, had affinities for sigma(1) or EBP of <60 nM.

Visualization of the domain structure of an L-type Ca2+ channel using electron cryo-microscopy.

The three-dimensional structure of the skeletal muscle voltage-gated L-type calcium channel (Ca(v)1.1; dihydropyridine receptor, DHPR) was determined using electron cryo-microscopy and single-particle averaging. The structure shows a single channel complex with an approximate total molecular mass of 550 kDa, corresponding to the five known subunits of the DHPR, and bound detergent and lipid.

Cloning of an emopamil-binding protein (EBP)-like protein that lacks sterol delta8-delta7 isomerase activity.

EBP (emopamil-binding protein) is a high-affinity binding protein for [3H]emopamil and belongs to the family of so-called sigma receptors. Mutations that disrupt EBP's 3beta-hydroxysteroid sterol delta8-delta7 isomerase activity (EC 5.3.

Functional consequences of P/Q-type Ca2+ channel Cav2.1 missense mutations associated with episodic ataxia type 2 and progressive ataxia.

We have investigated the functional consequences of three P/Q-type Ca(2+) channel alpha1A (Ca(v)2.1alpha(1)) subunit mutations associated with different forms of ataxia (episodic ataxia type 2 (EA-2), R1279Stop, AY1593/1594D; progressive ataxia (PA), G293R). Mutations were introduced into human alpha1A cDNA and heterologously expressed in Xenopus oocytes or tsA-201 cells (with alpha(2)delta and beta1a) for electrophysiological and biochemical analysis.

7-Dehydrocholesterol-dependent proteolysis of HMG-CoA reductase suppresses sterol biosynthesis in a mouse model of Smith-Lemli-Opitz/RSH syndrome.

Smith-Lemli-Opitz/RSH syndrome (SLOS), a relatively common birth-defect mental-retardation syndrome, is caused by mutations in DHCR7, whose product catalyzes an obligate step in cholesterol biosynthesis, the conversion of 7-dehydrocholesterol to cholesterol. A null mutation in the murine Dhcr7 causes an identical biochemical defect to that seen in SLOS, including markedly reduced tissue cholesterol and total sterol levels, and 30- to 40-fold elevated concentrations of 7-dehydrocholesterol. Prenatal lethality was not noted, but newborn homozygotes breathed with difficulty, did not suckle, and died soon after birth with immature lungs, enlarged bladders, and, frequently, cleft palates.

alpha 1D (Cav1.3) subunits can form l-type Ca2+ channels activating at negative voltages.

In cochlea inner hair cells (IHCs), L-type Ca(2+) channels (LTCCs) formed by alpha1D subunits (D-LTCCs) possess biophysical and pharmacological properties distinct from those of alpha1C containing C-LTCCs. We investigated to which extent these differences are determined by alpha1D itself by analyzing the biophysical and pharmacological properties of cloned human alpha1D splice variants in tsA-201 cells. Variant alpha1D(8A,) containing exon 8A sequence in repeat I, yielded alpha1D protein and L-type currents, whereas no intact protein and currents were observed after expression with exon 8B.

Mechanism of dihydropyridine interaction with critical binding residues of L-type Ca2+ channel alpha 1 subunits.

We investigated the mechanism of interaction of individual L-type channel amino acid residues with dihydropyridines within a dihydropyridine-sensitive alpha1A subunit (alpha1A(DHP)). Mutation of individual residues in repeat III and expression in Xenopus oocytes revealed that Thr(1393) is not required for dihydropyridine interaction but that bulky side chains (tyrosine, phenylalanine) in this position sterically inhibit dihydropyridine coordination. In position 1397 a side chain carbonyl group was required for high antagonist sensitivity.

Expression of the purported sigma(1) (sigma(1)) receptor in the mammalian brain and its possible relevance in deficits induced by antagonism of the NMDA receptor complex as revealed using an antisense strategy.

Sigma (sigma) receptors have generated a great deal of interest on the basis of their possible role in psychosis, neuroprotection and various other behaviors including learning processes. The existence of at least two classes of sigma receptor binding sites (sigma(1) and sigma(2)) is now well established. The recent cloning of the mouse, guinea pig and human sigma(1) receptors has allowed the study of the discrete distribution of the sigma(1) receptor mRNA in rodent and human brain tissues using in situ hybridization.