Type 2 diabetes mellitus (T2DM) continues to be a substantial medical problem due to its increasing global prevalence and because chronic hyperglycemic states are closely linked with obesity, liver disease and several cardiovascular diseases. Since the early discovery of insulin, numerous antihyperglycemic drug therapies to treat diabetes have been approved, and also discontinued, by the United States Food and Drug Administration (FDA). To provide an up-to-date account of the current trends of antidiabetic pharmaceuticals, this review offers a comprehensive analysis of the main classes of antihyperglycemic compounds and their mechanisms: insulin types, biguanides, sulfonylureas, meglitinides (glinides), alpha-glucosidase inhibitors (AGIs), thiazolidinediones (TZD), incretin-dependent therapies, sodium-glucose cotransporter type 2 (SGLT2) inhibitors and combinations thereof. The number of therapeutic alternatives to treat T2DM are increasing and now there are nearly 60 drugs approved by the FDA. Beyond this there are nearly 100 additional antidiabetic agents being evaluated in clinical trials. In addition to the standard treatments of insulin therapy and metformin, there are new drug combinations, e.g., containing metformin, SGLT2 inhibitors and dipeptidyl peptidase-4 (DPP4) inhibitors, that have gained substantial use during the last decade. Furthermore, there are several interesting alternatives, such as lobeglitazone, efpeglenatide and tirzepatide, in ongoing clinical trials. Modern drugs, such as glucagon-like peptide-1 (GLP-1) receptor agonists, DPP4 inhibitors and SGLT2 inhibitors have gained popularity on the pharmaceutical market, while less expensive over the counter alternatives are increasing in developing economies. The large heterogeneity of T2DM is also creating a push towards more personalized and accessible treatments. We describe several interesting alternatives in ongoing clinical trials, which may help to achieve this in the near future.

In recent years, the introduction of new molecular techniques in experimental and clinical settings has allowed researchers and clinicians to propose circulating-tumor DNA (ctDNA) analysis and liquid biopsy as novel promising strategies for the early diagnosis of cancer and for the definition of patients’ prognosis. It was widely demonstrated that through the non-invasive analysis of ctDNA, it is possible to identify and characterize the mutational status of tumors while avoiding invasive diagnostic strategies. Although a number of studies on ctDNA in patients’ samples significantly contributed to the improvement of oncology practice, some investigations generated conflicting data about the diagnostic and prognostic significance of ctDNA. Hence, to highlight the relevant achievements obtained so far in this field, a clearer description of the current methodologies used, as well as the obtained results, are strongly needed. On these bases, this review discusses the most relevant studies on ctDNA analysis in cancer, as well as the future directions and applications of liquid biopsy. In particular, special attention was paid to the early diagnosis of primary cancer, to the diagnosis of tumors with an unknown primary location, and finally to the prognosis of cancer patients. Furthermore, the current limitations of ctDNA-based approaches and possible strategies to overcome these limitations are presented.

Background Salivary cell secretion (SCS) plays a critical role in blood feeding by medicinal leeches, making them of use for certain medical purposes even today. Results We annotated the Hirudo medicinalis genome and performed RNA-seq on salivary cells isolated from three closely related leech species, H. medicinalis, Hirudo orientalis, and Hirudo verbana. Differential expression analysis verified by proteomics identified salivary cell-specific gene expression, many of which encode previously unknown salivary components. However, the genes encoding known anticoagulants have been found to be expressed not only in salivary cells. The function-related analysis of the unique salivary cell genes enabled an update of the concept of interactions between salivary proteins and components of haemostasis. Conclusions Here we report a genome draft of Hirudo medicinalis and describe identification of novel salivary proteins and new homologs of genes encoding known anticoagulants in transcriptomes of three medicinal leech species. Our data provide new insights in genetics of blood-feeding lifestyle in leeches.

a b s t r a c tThe heterodinuclear complexes [FeZn(L)(CH 3 CO 2 ) 2 ] + (L = ICIMP or IPCPMP) are structural models for the dinuclear active sites of plant purple acid phosphatases. They can be systematically synthesized from mononuclear iron complexes and enhance the rate of transesterification of 2-hydroxypropyl p-nitrophenyl phosphate, an assay for the catalytic hydrolysis performed by purple acid phosphatases.Ó 2009 Elsevier B.V. All rights reserved.The purple acid phosphatases catalyze the hydrolysis of phosphoesters at acidic pH. This class of enzymes contain active sites with dinuclear Fe(III)M(II) (M = Fe, Zn, Mn) cores [1], a number of which have been crystallographically characterized [2][3][4][5][6][7][8]. The structures of the active sites of the purple acid phosphatases isolated from plants are closely related and contain one iron and one zinc ion about 3.0-3.4 Å apart. The metals are ligated by histidines, tyrosines and carboxylate-containing amino acid residues and bridged by one of the carboxylate oxygens of an aspartate and a water or hydroxide molecule.The publication of the crystal structure of kidney bean purple acid phosphatase (kbPAP) [2] has provided impetus for the preparation of model complexes that may aid in the elucidation of the catalytic mechanism of this and related enzymes. Thus, FeZn complexes based on dinucleating ligands that contain a central bridging phenolate moiety have been published [9][10][11][12][13][14][15][16][17][18][19]. These model complexes have been prepared by simultaneous or stepwise addition of one equivalent of each metal salt. Here, we wish to present the controlled stepwise assembly of model complexes for kbPAP that not only contain an unsymmetric coordination environment, but also provide a vacant coordination site on one metal.The unsymmetric ligands H 2 ICIMP and H 2 IPCPMP (Fig. 1) have been shown to stabilize dinuclear species [20-22]. Addition of Fe (ClO 4 ) 3 (1-2 equivalents) to H 2 ICIMP in methanol, or FeCl 3 to an acetonitrile solution of H 4 IPCPMP(PF 6 ) 2 , yields purple solutions. The purple color indicates coordination of the phenolate moieties of the unsymmetric ligands; the color arises from the phenolate? Fe(III) LMCT electronic transition. Deep purple single crystals of the products [Fe(H 2 ICIMP)(H 2 O)Cl][Fe(H 2 ICIMP)(MeOH)Cl] [ClO 4 ] 4 (1) and [Fe(H 2 IPCPMP)Cl 2 ][PF 6 ] (2) [23] could be grown and their structures were determined by X-ray diffraction (Fig. 2) [24]. The structure of 1 contains two separate octahedrally coordinated Fe(ICIMP) molecules, which only differ in the bound solvent molecules (water or methanol). The iron(III) ion is in both cases located in the tetradentate pocket of the ligand, in keeping with the chelate effect. Another reason for the site preference may be the preference of the hard iron(III) ion for the hard carboxylate oxygen donor [25]. It is likely that the chloride ion originates from the ligand, which was isolated as a hydrochloride salt [26]. The crystal structure of 2 (Fig. 2, bottom) reveals an e...

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