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Uterine fibroids are the commonest benign tumours of women and affect all races with a cumulative lifetime risk of around 70%. Despite their high prevalence and the heavy economic burden of treatment, fibroids have received remarkably little attention compared to common female malignant tumours. This article reviews recent progress in understanding the biological nature of fibroids, their life cycle and their molecular genetic origins. Recent progress in surgical and interventional management is briefly reviewed, and medical management options, including treatment with selective progesterone receptor modulators, are also discussed.

Over the last three decades, short- and long-term observational studies, clinical trials, systematic reviews, and meta-analyses have provided relevant information on the efficacy and safety of growth hormone (GH) replacement therapy in adults with GH deficiency (AGHD). The knowledge acquired during this time has been compiled into different guidelines that offer clinicians an evidence-based, practical approach for the management of AGHD. There are, however, still open questions in some key areas in which recommendations are supported by only moderate or weak evidence. In the last recent years, the development of long-acting GH preparations has created new therapeutic possibilities by decreasing injection frequency, improving adherence and thereby potentially maximizing clinical outcomes. The aims of this review are to advance our understanding on the diagnosis and treatment of AGHD and to present an update and future perspectives on the use of long-acting GH preparations.

The treatment of type 2 diabetes mellitus has evolved in the present century toward safer and maybe more effective drugs, which in some cases can also reduce the risk of cardiovascular and renal outcomes. Nevertheless, we still need better strategies to reduce excess body weight in order to achieve diabetes remission, which is now a feasible target, as has been demonstrated with bariatric surgery. This review focuses on the significant advances in the management of blood glucose in type 2 diabetes mellitus, including the current understanding of the mechanisms of drug action but keeping in mind that the treatment of the disease is multifactorial.

Calcium and phosphate are critical for a myriad of physiological and cellular processes within the organism. Consequently, plasma levels of calcium and phosphate are tightly regulated. This occurs through the combined effects of the phospho- and calciotropic hormones, parathyroid hormone (PTH), active vitamin D 3, and fibroblast growth factor 23 (FGF23). The organs central to this are the kidneys, intestine, and bone. In the kidney, the proximal tubule reabsorbs the majority of filtered calcium and phosphate, which amounts to more than 60% and 90%, respectively. The basic molecular mechanisms responsible for phosphate reclamation are well described, and emerging work is delineating the molecular identity of the paracellular shunt wherein calcium permeates the proximal tubular epithelium. Significant experimental work has delineated the molecular effects of PTH and FGF23 on these processes as well as their regulation of active vitamin D 3 synthesis in this nephron segment. The integrative effects of both phospho- and calciotropic hormones on proximal tubular solute transport and subsequently whole body calcium-phosphate balance thus have been further complicated. Here, we first review the molecular mechanisms of calcium and phosphate reabsorption from the proximal tubule and how they are influenced by the phospho- and calciotropic hormones acting on this segment and then consider the implications on both renal calcium and phosphate handling as well as whole body mineral balance.

Obesity and insulin resistance often emerge from positive energy balance and generally are linked to low-grade inflammation. This low-grade inflammation has been called “meta-inflammation” because it is a consequence of the metabolic dysregulation that can accompany overnutrition. One means by which meta-inflammation is linked to insulin resistance is extracellular matrix expansion secondary to meta-inflammation, which we define here as “meta-fibrosis”. The significance of meta-fibrosis is that it reflects a situation in which the extracellular matrix functions as a multi-level integrator of local (for example, mitochondrial reactive oxygen species production) and systemic (for example, inflammation) inputs that couple to cellular processes creating insulin resistance. While adipose tissue extracellular matrix remodeling has received considerable attention, it is becoming increasingly apparent that liver and skeletal muscle extracellular matrix remodeling also contributes to insulin resistance. In this review, we address recent advances in our understanding of energy balance, mitochondrial energetics, meta-inflammation, and meta-fibrosis in the development of insulin resistance.

Orthologues of AMP-activated protein kinase (AMPK) occur in essentially all eukaryotes as heterotrimeric complexes comprising catalytic α subunits and regulatory β and γ subunits. The canonical role of AMPK is as an energy sensor, monitoring levels of the nucleotides AMP, ADP, and ATP that bind competitively to the γ subunit. Once activated, AMPK acts to restore energy homeostasis by switching on alternate ATP-generating catabolic pathways while switching off ATP-consuming anabolic pathways. However, its ancestral role in unicellular eukaryotes may have been in sensing of glucose rather than energy. In this article, we discuss a few interesting recent developments in the AMPK field. Firstly, we review recent findings on the canonical pathway by which AMPK is regulated by adenine nucleotides. Secondly, AMPK is now known to be activated in mammalian cells by glucose starvation by a mechanism that occurs in the absence of changes in adenine nucleotides, involving the formation of complexes with Axin and LKB1 on the surface of the lysosome. Thirdly, in addition to containing the nucleotide-binding sites on the γ subunits, AMPK heterotrimers contain a site for binding of allosteric activators termed the allosteric drug and metabolite (ADaM) site. A large number of synthetic activators, some of which show promise as hypoglycaemic agents in pre-clinical studies, have now been shown to bind there. Fourthly, some kinase inhibitors paradoxically activate AMPK, including one (SU6656) that binds in the catalytic site. Finally, although downstream targets originally identified for AMPK were mainly concerned with metabolism, recently identified targets have roles in such diverse areas as mitochondrial fission, integrity of epithelial cell layers, and angiogenesis.

A number of recent advances have been made in the epidemiology and treatment of chronic granulomatous disease. Several reports from developing regions describe the presentations and progress of local populations, highlighting complications due to Bacillus Calmette–Guérin vaccination. A number of new reports describe complications of chronic granulomatous disease in adult patients, as more survivors reach adulthood. The complications experienced by X-linked carriers are particularly highlighted in three new reports, confirming that infection and inflammatory or autoimmune conditions are more common and severe than previously recognised. Finally, definitive treatment with haematopoietic stem cell transplantation and gene therapy is reviewed.

The accumulation of ‘senescent’ cells has long been proposed to act as an ageing mechanism. These cells display a radically altered transcriptome and degenerative phenotype compared with their growing counterparts. Tremendous progress has been made in recent years both in understanding the molecular mechanisms controlling entry into the senescent state and in the direct demonstration that senescent cells act as causal agents of mammalian ageing. The challenges now are to gain a better understanding of how the senescent cell phenotype varies between different individuals and tissues, discover how senescence predisposes to organismal frailty, and develop mechanisms by which the deleterious effects of senescent cells can be ameliorated.

Hereditary angioedema (HAE) with C1-inhibitor (C1-Inh) deficiency (C1-Inh-HAE) is a rare, life-threatening, and disabling genetic disorder characterized by self-limited tissue swelling caused by deficiency or dysfunction of C1-Inh. Our aim in this update is to discuss new advances in HAE therapy, focusing mainly on the various treatment options that have become available recently and also drugs that are under trial for prophylaxis to prevent attacks. There is a paradigm shift to where the treatment of HAE is headed, focusing now on prophylactic treatment rather than abortive management.

Metabolomics is the newest addition to the “omics” disciplines and has shown rapid growth in its application to human health research because of fundamental advancements in measurement and analysis techniques. Metabolomics has unique and proven advantages in systems biology and biomarker discovery. The next generation of analysis techniques promises even richer and more complete analysis capabilities that will enable earlier clinical diagnosis, drug refinement, and personalized medicine. A review of current advancements in methodologies and statistical analysis that are enhancing and improving the performance of metabolomics is presented along with highlights of some recent successful applications.

Pancreatic neuroendocrine tumors (PanNETs) manifest with a range of symptoms and pose a therapeutic challenge. A team approach, in which many specialists come together, is necessary in the quest for the best patient-tailored treatment. Disciplines such as oncology, surgery, basic science, endocrinology, radiology, and nuclear medicine need to work side by side, equally contributing to patient care and to advancing our better understanding of this fascinating disease.

There has been substantial progress in the management of patients with osteoporosis and the prevention of osteoporotic fractures. Currently available strong anti-resorptive agents are bisphosphonates and an anti-receptor activator of nuclear factor-kappa B ligand (RANKL) antibody, denosumab. Although bisphosphonates and denosumab both inhibit bone resorption and prevent vertebral and non-vertebral fractures, their mechanisms of action are different. Whereas bisphosphonates’ effects on bone mineral density and fracture peak around 3 to 5 years and become plateaued, those of denosumab are maintained for up to 10 years. There are differences in the modes of action of these two drugs. Bisphosphonates accumulate on the mineralized bone surface and are released by the acid environment under osteoclastic bone resorption, whereas denosumab is not accumulated on bone but directly binds RANKL and inhibits its binding to the receptor RANK. Thus, the reduction in denosumab concentration 4 to 6 months after injection may enable RANK to bind to RANKL, where it is highly expressed, such as in damaged bone regions. As anabolic agents, only teriparatide has been available for a long time, but abaloparatide, a synthetic analog of PTHrP(1–34), is currently under development. Because of the difference in the preferential binding conformations of PTH1 receptor between teriparatide and abaloparatide, the latter shows anabolic effects with fewer bone resorptive effects. Romosozumab, an anti-sclerostin antibody, inhibits the action of sclerostin, a canonical Wnt signal inhibitor secreted from osteocytes, and enhances canonical Wnt signaling. Romosozumab robustly increases vertebral and proximal femoral bone mineral density within 12 months and inhibits vertebral and clinical fractures in patients with osteoporosis by enhancing bone formation and inhibiting bone resorption. In this review, we summarize the recent advances in therapeutic agents for the treatment of osteoporosis and discuss future prospects with their use.

Cushing’s disease is a rare disease with a characteristic phenotype due to significant hypercortisolism driven by over-secretion of adrenocorticotropic hormone and to high morbidity and mortality if untreated. It is caused by a corticotroph adenoma of the pituitary, but the exact mechanisms leading to tumorigenesis are not clear. Recent advances in molecular biology such as the discovery of somatic mutations of the ubiquitin-specific peptidase 8 ( USP8) gene allow new insights into the pathogenesis, which could be translated into exciting and much-needed therapeutic applications.

Hypertension, or high blood pressure, is a prevalent yet modifiable risk factor for cardiovascular disease. While there are many effective treatments available to combat hypertension, patients often require at least two to three medications to control blood pressure, although there are patients who are resistant to such therapies. This short review will briefly update on recent clinical advances and potential emerging therapies and is intended for a cross-disciplinary readership.

The extracellular calcium-sensing receptor (CaR), a ubiquitous class C G-protein-coupled receptor (GPCR), is responsible for the control of calcium homeostasis in body fluids. It integrates information about external Ca 2+ and a surfeit of other endogenous ligands into multiple intracellular signals, but how is this achieved? This review will focus on some of the exciting concepts in CaR signaling and pharmacology that have emerged in the last few years.

The ongoing worldwide obesity epidemic makes the metabolic syndrome an increasingly important entity. In this review, we provide a short background on the metabolic syndrome, we discuss recent developments in the three main options that have been identified for intervention in the metabolic syndrome, i.e. lifestyle and surgical and pharmacological interventions, and we focus on different views in the literature and also include our own viewpoints on the metabolic syndrome. In addition, we discuss some emerging treatment targets for adipose tissue dysfunction and low-grade inflammation, i.e. activation of the inflammasome and the complement system, and consider some selected opportunities for intervention in these processes.

The ability of humans to sense chemical signals in ingested substances is implicit in the ability to detect the five basic tastes; sweet, sour, bitter, salty, and umami. Of these, sweet, bitter, and umami tastes are detected by lingual G-protein-coupled receptors (GPCRs). Recently, these receptors were also localized to the gut mucosa. In this review, we will emphasize recent advances in the understanding of the mechanisms and consequences of foregut luminal chemosensing, with special emphasis on cell surface GPCRs such as the sweet and proteinaceous taste receptors (TASRs), short- and long-chain fatty acid (FA) receptors, and bile acid receptors. The majority of these luminal chemosensors are expressed on enteroendocrine cells (EECs), which are specialized endocrine cells in the intestine and pancreas that release gut hormones with ligand activation. These gut hormones are responsible for a wide variety of physiologic and homeostatic mechanisms, including glycemic control, appetite stimulation and suppression, regulation of gastric emptying, and trophic effects on the intestinal epithelium. Released from the EECs, the gut peptides have paracrine, autocrine, and endocrine effects. Additionally, EECs have unique direct connections to the enteric nervous system enabling precise transmission of sensory data to and communication with the central nervous system. We will also describe how gut sensors are implicated in gut hormone release, followed by examples of how altered gut chemosensing has been implicated in pathological conditions such as metabolic diseases including diabetes and obesity, functional dyspepsia, helminthic infections, colitis, gastric bypass surgery, and gastric inflammation and cancer.

Diabetic nephropathy is the commonest cause of end-stage renal disease in most developed economies. Current standard of care for diabetic nephropathy embraces stringent blood pressure control via blockade of the renin-angiotensin-aldosterone system and glycemia control. Recent understanding of the pathophysiology of diabetic nephropathy has led to the development of novel therapeutic options. This review article focuses on available data from landmark studies on the main therapeutic approaches and highlights some novel management strategies.

Diabetes has become one of the largest global health-care problems of the 21 st century. According to the Centers for Disease Control and Prevention, the population prevalence of diabetes in the US is approaching 10% and is increasing by 5% each year. Diabetic neuropathy is the most common complication associated with diabetes mellitus. Diabetes causes a broad spectrum of neuropathic complications, including acute and chronic forms affecting each level of the peripheral nerve, from the root to the distal axon. This review will focus on the most common form, distal symmetric diabetic polyneuropathy. There has been an evolution in our understanding of the pathophysiology and the management of diabetic polyneuropathy over the past decade. We highlight these new perspectives and provide updates from the past decade of research.

Research focusing on type 1 diabetes (T1D) autoantigens aims to explore our understanding of these beta cell proteins in order to design assays for monitoring the pathogenic autoimmune response, as well as safe and efficient therapies preventing or stopping it. In this review, we will discuss progress made in the last 5 years with respect to mechanistic understanding, diagnostic monitoring, and therapeutic modulation of the autoantigen-specific cellular immune response in T1D. Some technical progress in monitoring tools has been made; however, the potential of recent technologies for highly multiplexed exploration of human cellular immune responses remains to be exploited in T1D research, as it may be the key to the identification of surrogate markers of disease progression that are still wanting. Detailed analysis of autoantigen recognition by T cells suggests an important role of non-conventional antigen presentation and processing in beta cell-directed autoimmunity, but the impact of this in human T1D has been little explored. Finally, therapeutic administration of autoantigens to T1D patients has produced disappointing results. The application of novel modes of autoantigen administration, careful translation of mechanistic understanding obtained in preclinical studies and in vitro with human cells, and combination therapies including CD3 antibodies may help to make autoantigen-based immunotherapy for T1D a success story in the future.

Large controlled clinical trials have demonstrated reductions with statin therapy in cardiovascular events in patients presenting with acute coronary syndromes and stable coronary heart disease and individuals at high risk of a cardiovascular event. In trials of acute coronary syndromes and stable coronary heart disease, high-intensity statin therapy is more effective in the prevention of recurrent cardiovascular events than low-intensity statin therapy. Thus, evidence-based guidelines recommend in-hospital initiation of high-intensity statin therapy for all acute coronary syndrome patients. Clinical trials report high adherence to and low discontinuation of high-intensity statin therapy; however, in clinical practice, high-intensity statins are prescribed to far fewer patients, who often discontinue their statin after the first refill. A coordinated effort among the patient, provider, pharmacist, health system, and insurer is necessary to improve utilization and persistence of prescribed medications. The major cause for statin discontinuations reported by patients is perceived adverse events. Evaluation of potential adverse events requires validated tools to distinguish between statin-associated adverse events versus non-specific complaints. Treatment options for statin-intolerant patients include the use of a different statin, often at a lower dose or frequency. In order to lower LDL cholesterol, lower doses of statins may be combined with ezetimibe or bile acid sequestrants. Newer treatment options for patients with statin-associated muscle symptoms may include proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors.

Metabolic acidosis could emerge from diseases disrupting acid-base equilibrium or from drugs that induce similar derangements. Occurrences are usually accompanied by comorbid conditions of drug-induced metabolic acidosis, and clinical outcomes may range from mild to fatal. It is imperative that clinicians not only are fully aware of the list of drugs that may lead to metabolic acidosis but also understand the underlying pathogenic mechanisms. In this review, we categorized drug-induced metabolic acidosis in terms of pathophysiological mechanisms, as well as individual drugs’ characteristics.

Primary immunodeficiencies are rare, inborn errors that result in impaired, disordered or uncontrolled immune responses. Whilst symptomatic and prophylactic treatment is available, hematopoietic stem cell transplantation is an option for many diseases, leading to cure of the immunodeficiency and establishing normal physical and psychological health. Newborn screening for some diseases, whilst improving outcomes, is focusing research on safer and less toxic treatment strategies, which result in durable and sustainable immune function without adverse effects. New conditioning regimens have reduced the risk of hematopoietic stem cell transplantation, and new methods of manipulating stem cell sources should guarantee a donor for almost all patients. Whilst incremental enhancements in transplantation technique have gradually improved survival outcomes over time, some of these new applications are likely to radically alter our approach to treating primary immunodeficiencies.

When patients seek medical care, they assume the treatment or advice they receive is based on a strong understanding of the human body and its processes. They also typically assume the care they receive is based on a strong understanding of the research literature pertaining to their well-being and any ailments for which they might seek care. However, publication bias and inadequate research transparency greatly threaten medical providers’ ability to practice evidence-based medicine in its truest form, and this in turn puts patients at unnecessary risk. The evidence of these issues existing is unequivocal. However, systematic reviews and other studies that present overviews of these issues – although certainly incredibly important in establishing the undeniable presence and pervasiveness of these issues – may inadvertently obfuscate the concreteness of these closely-related processes in action. Therefore, this article presents a “case series” of these detrimental issues in action in an effort to emphasize the tangibility of these issues and thereby help make their importance unmistakably clear.

Cancer chemoprevention refers to the use of agents for the inhibition, delay, or reversal of carcinogenesis before invasion. In the present review, agents examined in the context of cancer chemoprevention are classified in four major categories—hormonal, medications, diet-related agents, and vaccines—and the main representatives of each category are presented. Although there are serious constraints in the documentation of effectiveness of chemopreventive agents, mainly stemming from the long latency of the condition they are addressing and the frequent lack of intermediate biomarkers, there is little disagreement about the role of aspirin, whereas a diet rich in vegetables and fruits appears to convey more protection than individual micronutrients. Among categories of cancer chemopreventive agents, hormonal ones and vaccines might hold more promise for the future. Also, the identification of individuals who would benefit most from chemopreventive interventions on the basis of their genetic profiles could open new prospects for cancer chemoprevention.

Osteogenesis imperfecta (OI) is an uncommon genetic bone disease associated with brittle bones and fractures in children and adults. Although OI is most commonly associated with mutations of the genes for type I collagen, many other genes (some associated with type I collagen processing) have now been identified. The genetics of OI and advances in our understanding of the biomechanical properties of OI bone are reviewed in this article. Treatment includes physiotherapy, fall prevention, and sometimes orthopedic procedures. In this brief review, we will also discuss current understanding of pharmacologic therapies for treatment of OI.

When patients seek medical care, they assume the treatment or advice they receive is based on a strong understanding of the human body and its processes. They also typically assume the care they receive is based on a strong understanding of the research literature pertaining to their well-being and any ailments for which they might seek care. However, publication bias and inadequate research transparency greatly threaten medical providers’ ability to practice evidence-based medicine in its truest form, and this in turn puts patients at unnecessary risk. The evidence of these issues existing is unequivocal. However, systematic reviews and other studies that present overviews of these issues – although certainly incredibly important in establishing the undeniable presence and pervasiveness of these issues – may inadvertently obfuscate the concreteness of these closely-related processes in action. Therefore, this article presents a “case series” of these detrimental issues in action in an effort to emphasize the tangibility of these issues and thereby help make their importance unmistakably clear.

Congenital adrenal hyperplasia associated with deficiency of steroid 21-hydroxylase is the most common inborn error in adrenal function and the most common cause of adrenal insufficiency in the pediatric age group. As patients now survive into adulthood, adult health-care providers must also be familiar with this condition. Over the past several years, F1000 has published numerous commentaries updating research and practical guidelines for this condition. The purposes of this review are to summarize basic information defining congenital adrenal hyperplasia and to highlight current knowledge and controversies in management.

The long term side effects of any newly introduced drug is a subject of intense research, and often raging controversies. One such example is the dipeptidyl peptidase-IV (DPP4) inhibitor used for treating type 2 diabetes, which is inconclusively implicated in increased susceptibility to acute pancreatitis. Previously, based on a computational analysis of the spatial and electrostatic properties of active site residues, we have demonstrated that phosphoinositide-specific phospholipase C (PI-PLC) from Bacillus cereus is a prolyl peptidase using in vivo experiments. In the current work, we first report the inhibition of the native activity of PI-PLC by two DPP4 inhibitors - vildagliptin (LAF-237) and K-579. While vildagliptin inhibited PI-PLC at micromolar concentrations, K-579 was a potent inhibitor even at nanomolar concentrations. Subsequently, we queried a comprehensive, non-redundant set of 5000 human proteins (50% similarity cutoff) with known structures using serine protease (SPASE) motifs derived from trypsin and DPP4. A pancreatic lipase and a gastric lipase are among the proteins that are identified as proteins having promiscuous SPASE scaffolds that could interact with DPP4 inhibitors. The presence of such scaffolds in human lipases is expected since they share the same catalytic mechanism with PI-PLC. However our methodology also detects other proteins, often with a completely different enzymatic mechanism, that have significantly congruent domains with the SPASE motifs. The reported elevated levels of serum lipase, although contested, could be rationalized by inhibition of lipases reported here. In an effort to further our understanding of the spatial and electrostatic basis of DPP4 inhibitors, we have also done a comprehensive analysis of all 76 known DPP4 structures liganded to inhibitors till date. Also, the methodology presented here can be easily adopted for other drugs, and provide the first line of filtering in the identification of pathways that might be inadvertently affected due to promiscuous scaffolds in proteins.

The long term side effects of any newly introduced drug is a subject of intense research, and often raging controversies. One such example is the dipeptidyl peptidase-IV (DPP4) inhibitor used for treating type 2 diabetes, which is inconclusively implicated in increased susceptibility to acute pancreatitis. Previously, based on a computational analysis of the spatial and electrostatic properties of active site residues, we have demonstrated that phosphoinositide-specific phospholipase C (PI-PLC) from Bacillus cereus is a prolyl peptidase using in vivo experiments. In the current work, we first report the inhibition of the native activity of PI-PLC by two DPP4 inhibitors - vildagliptin (LAF-237) and K-579. While vildagliptin inhibited PI-PLC at micromolar concentrations, K-579 was a potent inhibitor even at nanomolar concentrations. Subsequently, we queried a comprehensive, non-redundant set of 5000 human proteins (50% similarity cutoff) with known structures using serine protease (SPASE) motifs derived from trypsin and DPP4. A pancreatic lipase and a gastric lipase are among the proteins that are identified as proteins having promiscuous SPASE scaffolds that could interact with DPP4 inhibitors. The presence of such scaffolds in human lipases is expected since they share the same catalytic mechanism with PI-PLC. However our methodology also detects other proteins, often with a completely different enzymatic mechanism, that have significantly congruent domains with the SPASE motifs. The reported elevated levels of serum lipase, although contested, could be rationalized by inhibition of lipases reported here. In an effort to further our understanding of the spatial and electrostatic basis of DPP4 inhibitors, we have also done a comprehensive analysis of all 76 known DPP4 structures liganded to inhibitors till date. Also, the methodology presented here can be easily adopted for other drugs, and provide the first line of filtering in the identification of pathways that might be inadvertently affected due to promiscuous scaffolds in proteins.

The long term side effects of any newly introduced drug is a subject of intense research, and often raging controversies. One such example is the dipeptidyl peptidase-IV (DPP4) inhibitor used for treating type 2 diabetes, which is inconclusively implicated in increased susceptibility to acute pancreatitis. Previously, based on a computational analysis of the spatial and electrostatic properties of active site residues, we have demonstrated that phosphoinositide-specific phospholipase C (PI-PLC) from Bacillus cereus is a prolyl peptidase using in vivo experiments. In the current work, we first report the inhibition of the native activity of PI-PLC by two DPP4 inhibitors - vildagliptin (LAF-237) and K-579. While vildagliptin inhibited PI-PLC at micromolar concentrations, K-579 was a potent inhibitor even at nanomolar concentrations. Subsequently, we queried a comprehensive, non-redundant set of 5000 human proteins (50% similarity cutoff) with known structures using serine protease (SPASE) motifs derived from trypsin and DPP4. A pancreatic lipase and a gastric lipase are among the proteins that are identified as proteins having promiscuous SPASE scaffolds that could interact with DPP4 inhibitors. The presence of such scaffolds in human lipases is expected since they share the same catalytic mechanism with PI-PLC. However our methodology also detects other proteins, often with a completely different enzymatic mechanism, that have significantly congruent domains with the SPASE motifs. The reported elevated levels of serum lipase, although contested, could be rationalized by inhibition of lipases reported here. In an effort to further our understanding of the spatial and electrostatic basis of DPP4 inhibitors, we have also done a comprehensive analysis of all 76 known DPP4 structures liganded to inhibitors till date. Also, the methodology presented here can be easily adopted for other drugs, and provide the first line of filtering in the identification of pathways that might be inadvertently affected due to promiscuous scaffolds in proteins.

The long term side effects of any newly introduced drug is a subject of intense research, and often raging controversies. One such example is the dipeptidyl peptidase-IV (DPP4) inhibitor used for treating type 2 diabetes, which is inconclusively implicated in increased susceptibility to acute pancreatitis. Previously, based on a computational analysis of the spatial and electrostatic properties of active site residues, we have demonstrated that phosphoinositide-specific phospholipase C (PI-PLC) from Bacillus cereus is a prolyl peptidase using in vivo experiments. In the current work, we first report the inhibition of the native activity of PI-PLC by two DPP4 inhibitors - vildagliptin (LAF-237) and K-579. While vildagliptin inhibited PI-PLC at micromolar concentrations, K-579 was a potent inhibitor even at nanomolar concentrations. Subsequently, we queried a comprehensive, non-redundant set of 5000 human proteins (50% similarity cutoff) with known structures using serine protease (SPASE) motifs derived from trypsin and DPP4. A pancreatic lipase and a gastric lipase are among the proteins that are identified as proteins having promiscuous SPASE scaffolds that could interact with DPP4 inhibitors. The presence of such scaffolds in human lipases is expected since they share the same catalytic mechanism with PI-PLC. However our methodology also detects other proteins, often with a completely different enzymatic mechanism, that have significantly congruent domains with the SPASE motifs. The reported elevated levels of serum lipase, although contested, could be rationalized by inhibition of lipases reported here. In an effort to further our understanding of the spatial and electrostatic basis of DPP4 inhibitors, we have also done a comprehensive analysis of all 76 known DPP4 structures liganded to inhibitors till date. Also, the methodology presented here can be easily adopted for other drugs, and provide the first line of filtering in the identification of pathways that might be inadvertently affected due to promiscuous scaffolds in proteins.

The long term side effects of any newly introduced drug is a subject of intense research, and often raging controversies. One such example is the dipeptidyl peptidase-IV (DPP4) inhibitor used for treating type 2 diabetes, which is inconclusively implicated in increased susceptibility to acute pancreatitis. Previously, based on a computational analysis of the spatial and electrostatic properties of active site residues, we have demonstrated that phosphoinositide-specific phospholipase C (PI-PLC) from Bacillus cereus is a prolyl peptidase using in vivo experiments. In the current work, we first report the inhibition of the native activity of PI-PLC by two DPP4 inhibitors - vildagliptin (LAF-237) and K-579. While vildagliptin inhibited PI-PLC at micromolar concentrations, K-579 was a potent inhibitor even at nanomolar concentrations. Subsequently, we queried a comprehensive, non-redundant set of 5000 human proteins (50% similarity cutoff) with known structures using serine protease (SPASE) motifs derived from trypsin and DPP4. A pancreatic lipase and a gastric lipase are among the proteins that are identified as proteins having promiscuous SPASE scaffolds that could interact with DPP4 inhibitors. The presence of such scaffolds in human lipases is expected since they share the same catalytic mechanism with PI-PLC. However our methodology also detects other proteins, often with a completely different enzymatic mechanism, that have significantly congruent domains with the SPASE motifs. The reported elevated levels of serum lipase, although contested, could be rationalized by inhibition of lipases reported here. Also, the methodology presented here can be easily adopted for other drugs, and provide the first line of filtering in the identification of pathways that might be inadvertently affected due to promiscuous scaffolds in proteins.

Background: Corticosteroids are widely prescribed products in the elderly particularly in systemic diseases and have been indispensable in controlling a variety of disease states. The various complications associated with this drug class warrant caution and monitoring with each formulation, especially with an older patient population. Aim: The aim of our study was to evaluate the frequency and type of side effects and complications of long-term corticosteroid therapy in the elderly. Methods: We conducted a retrospective study of 23 patients aged 65 and older hospitalized in the Internal Medicine Department of the Habib Thameur hospital from January 2000 to December 2004. Corticoid-related adverse effects were recorded throughout the follow-up period. Results: There were 20 women and 3 men aged 66 to 87 years with a mean age of 75.7 years. The diagnoses were 8 cases of temporal arteritis, 7 cases of rheumatoid arthritis, 3 cases of multiple myeloma, 2 scleroderma, 1 case of systemic lupus erythematosus, 1 case of retroperitoneal fibrosis and 1 case of psoriatic arthritis. We selected 66 complications. Infectious complications were found in 26 cases (39.3%), 11 cases (16.7%) of iatrogenic diabetes, arterial hypertension in 9 cases (13%), skeletal complications in two cases, psychiatric complications in two cases, ophthalmologic complications in one case. Conclusion: Despite lifestyle rules and adjunctive therapy, complications seem to be frequent. To minimize the disadvantages of prolonged corticosteroid treatment, regular monitoring and careful screening is imperative to detect and handle them in time.

The extracellular calcium-sensing receptor (CaR), a ubiquitous class C G-protein-coupled receptor (GPCR), is responsible for the control of calcium homeostasis in body fluids. It integrates information about external Ca 2+ and a surfeit of other endogenous ligands into multiple intracellular signals, but how is this achieved? This review will focus on some of the exciting concepts in CaR signaling and pharmacology that have emerged in the last few years.

Cancer chemoprevention refers to the use of agents for the inhibition, delay, or reversal of carcinogenesis before invasion. In the present review, agents examined in the context of cancer chemoprevention are classified in four major categories—hormonal, medications, diet-related agents, and vaccines—and the main representatives of each category are presented. Although there are serious constraints in the documentation of effectiveness of chemopreventive agents, mainly stemming from the long latency of the condition they are addressing and the frequent lack of intermediate biomarkers, there is little disagreement about the role of aspirin, whereas a diet rich in vegetables and fruits appears to convey more protection than individual micronutrients. Among categories of cancer chemopreventive agents, hormonal ones and vaccines might hold more promise for the future. Also, the identification of individuals who would benefit most from chemopreventive interventions on the basis of their genetic profiles could open new prospects for cancer chemoprevention.