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  • Potential of glucocorticoids to treat intestinal inflammation during sepsis
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2020-01-25
    Kelly Van Looveren; Charlotte Wallaeys; Claude Libert

    Glucocorticoids (GCs) are steroid hormones characterized by their anti-inflammatory and immunosuppressive nature. Although GCs are very commonly prescribed, in several diseases, including sepsis, their clinical treatment is hampered by side effects and by the occurrence of glucocorticoid resistance (GCR). Sepsis is defined as a life-threatening organ dysfunction, initiated by a dysregulated systemic host response to infections. With at least 19 million cases per year and a lethality rate of about 25%, sepsis is one of the most urgent unmet medical needs. The gut is critically affected during sepsis and is considered as a driving force in this disease. Despite there is no effective treatment for sepsis, pre-clinical studies show promising results by preserving or restoring gut integrity. Since GC treatment reveals therapeutic effects in Crohn’s disease (CD) and in pre-clinical sepsis models, we hypothesize that targeting GCs to the gut or stimulating local GC production in the gut forms an interesting strategy for sepsis treatment. According to recent findings that show that dimerization of the glucocorticoid receptor (GR) is essential in inducing anti-inflammatory effects in pre-clinical sepsis models, we predict that new generation GCs that selectively dimerize the GR, can therefore positively affect the outcome of sepsis treatment.

    更新日期:2020-01-26
  • Next-generation drug repurposing using human genetics and network biology
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2020-01-22
    Serguei Nabirotchkin; Alex E Peluffo; Philippe Rinaudo; Jinchao Yu; Rodolphe Hajj; Daniel Cohen

    Drug repurposing has attracted increased attention, especially in the context of drug discovery rates that remain too low despite a recent wave of approvals for biological therapeutics (e.g. gene therapy). These new biological entities-based treatments have high costs that are difficult to justify for small markets that include rare diseases. Drug repurposing, involving the identification of single or combinations of existing drugs based on human genetics data and network biology approaches represents a next-generation approach that has the potential to increase the speed of drug discovery at a lower cost. This Pharmacological Perspective reviews progress and perspectives in combining human genetics, especially genome-wide association studies, with network biology to drive drug repurposing for rare and common diseases with monogenic or polygenic etiologies. Also, highlighted here are important features of this next generation approach to drug repurposing, which can be combined with machine learning methods to meet the challenges of personalized medicine.

    更新日期:2020-01-23
  • Null hypothesis significance testing and effect sizes: can we ‘effect’ everything … or … anything?
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2020-01-14
    David P Lovell

    The Null Hypothesis Significance Testing (NHST) paradigm is increasingly criticized. Estimation approaches such as point estimates and confidence intervals, while having limitations, provide better descriptions of results than P-values and statements about significance levels. Their use is supported by many statisticians. The effect size approach is an important part of power and sample size calculations at the experimental design stage and in meta-analysis and in the interpretation of the biological importance of study results. Care is needed, however, to ensure that such effect sizes are relevant for the endpoint. Effect sizes should not be used to interpret results without accompanying limits, such as confidence intervals. New methods, especially Bayesian approaches, are being developed; however, no single method provides a simple answer. Rather there is a need to improve researchers understanding of the complex issues underlying experimental design, statistical analysis and interpretation of results.

    更新日期:2020-01-14
  • Histone deacetylases 1, 2 and 3 in nervous system development
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2020-01-02
    Santosh R D’Mello

    Although histone acetylases (HDACS) were initially believed to render chromatin in a transcriptionally repressed state by deacetylating histones, it is now known that they both repress and activate transcription. Moreover, HDACs regulate the activity and/or function of a large number of other cellular proteins localized in the nucleus and cytoplasm. Accumulating evidence indicates that HDACs also play a key role in the development of the nervous system. This review focuses on three classical HDACS — HDACs 1, 2 and 3. Although much evidence on the involvement of HDACs in neurodevelopment has come from the use of pharmacological inhibitors, because these agents are not specific in their action on individual HDAC proteins, this review only describes evidence derived from the use of molecular genetic approaches. Our review describes that HDACs 1, 2 and 3 play crucial roles in neurodevelopment by regulating neurogenesis, gliogenesis, the development of neural circuitry and synaptic transmission.

    更新日期:2020-01-02
  • Untangling human neurogenesis to understand and counteract brain disorders
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-12-31
    Ruth Beckervordersandforth; Chiara Rolando

    Neurogenesis in the human postnatal brain occurs in two regions, the subventricular zone of the later ventricle and the dentate gyrus of the hippocampus. While it is well accepted that SVZ and hippocampal neurogenesis are active during juvenile stages in human, their contribution during adulthood and ageing as well as pathological states is recently animating the neural stem cell research field. In this review we will discuss recent evidence about the organization of SVZ and hippocampal neurogenic niches, and will report on how human adult neurogenesis may contribute to disease and appears to respond to neurodegeneration. In light of these novel findings, we will discuss how we can target human adult neurogenesis in order to influence brain disease trajectories.

    更新日期:2019-12-31
  • Ependymal cells in the spinal cord as neuronal progenitors
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-12-31
    Victoria Moreno-Manzano

    Ependymal cells are neural progenitors and form part of the central canal of the spinal cord. Therefore, ependymal cells could serve as a potential source of neural progenitors for regenerative medicine applications. Such applications consist of endogenous activation or exogenous transplantation, alone or in combination with pharmacological treatments, to repair spinal cord injuries. This mini review describes the main phenotypical characteristics of ependymal cells from spinal cord and the opportunities offered for spinal cord injury therapeutic application.

    更新日期:2019-12-31
  • Understanding the effects of air pollution on neurogenesis and gliogenesis in the growing and adult brain
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-12-30
    Enrica Boda; Antonello E Rigamonti; Valentina Bollati

    Exposure to air pollution — and particularly to particulate matter (PM) – is strongly associated with higher risk of neurodevelopmental disorders, poor mental health and cognitive defects. In animal models, disruption of CNS development and disturbances of adult neurogenesis contribute to PM neurotoxicity. Recent studies show that gestational PM exposure not only affects embryonic neurodevelopment, but also disturbs postnatal brain growth and maturation, by interfering with neurogenic/gliogenic events, myelination and synaptogenesis. Similarly, adult neurogenesis is affected at many levels, from neural stem cell amplification up to the maturation and integration of novel neurons in the adult brain parenchyma. The underlying mechanisms are still by and large unknown. Beyond microglia activation and neuroinflammation, recent studies propose a role for novel epigenetic mechanisms, including DNA methylation and extracellular vesicles-associated microRNAs.

    更新日期:2019-12-30
  • NG2 cells and their neurogenic potential
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-12-24
    Denisa Kirdajova; Miroslava Anderova
    更新日期:2019-12-25
  • Nutrients and neurogenesis: the emerging role of autophagy and gut microbiota
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-12-20
    Virve Cavallucci; Marco Fidaleo; Giovambattista Pani

    Adult neurogenesis, the generation of mature functional neurons from neural stem cells in specific regions of the adult mammalian brain, is implicated in brain physiology, neurodegeneration and mood disorders. Among the many intrinsic and extrinsic factors that modulate neurogenic activity, the role of nutrients, energy metabolism, and gut microbiota has recently emerged. It is increasingly evident that excessive calorie intake accelerates the age-dependent decline of neurogenesis, while calorie restriction and physical exercise have the opposite effect. Mechanistically, nutrient availability could affect neurogenesis by modulating autophagy, a cell-rejuvenating process, in neural stem cells. In parallel, diet can alter the composition of gut microbiota thus impacting the intestine-neurogenic niche communication. These exciting breakthroughs are here concisely reviewed.

    更新日期:2019-12-20
  • New insights into the regulatory roles of microRNAs in adult neurogenesis
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-12-19
    Marta Esteves; Catarina Serra-Almeida; Cláudia Saraiva; Liliana Bernardino
    更新日期:2019-12-19
  • Endocannabinoid system and adult neurogenesis: a focused review
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-12-18
    Sergio Oddi; Lucia Scipioni; Mauro Maccarrone

    The endocannabinoid system (eCB) is a ubiquitous lipid signaling system composed of at least two receptors, their endogenous ligands, and the enzymes responsible for their synthesis and degradation. Within the brain, the eCB system is highly expressed in the hippocampus and controls basic biological processes, including neuronal proliferation, migration and differentiation, which are intimately linked with embryonal neurogenesis. Accumulated preclinical evidence has indicated that eCBs play a major role also in regulating adult neurogenesis. Increased cannabinoid receptor activity, either by increased eCB content or by pharmacological blockade of their degradation, produces neurogenic effects alongside rescue of phenotypes in animal models of different psychiatric and neurological disorders. Therefore, in the light of the higher therapeutic potential of adult neurogenesis compared to the embryonic one, here we sought to summarize the most recent evidence pointing towards a neurogenic role for eCBs in the adult brain, both under normal and pathological conditions.

    更新日期:2019-12-19
  • Impact of gut microbiota on neurogenesis and neurological diseases during infancy
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-12-18
    Tomás Cerdó; Estefanía Diéguez; Cristina Campoy

    The first years of life constitute a crucial period for neurodevelopment and a window of opportunity to develop new strategies to prevent neurological and mental diseases. Different studies have shown the influence of gut bacteria in neurogenesis and a functional relationship between gut microbiota and the brain, known as ‘gut–brain axis’, in which the intestinal microbiota is proposed to play a key role in neurophysiological processes. It has been observed that certain microbiome metabolites could be related to the development of neurological disorders through mechanisms still unknown. Then, more studies are needed to broaden the knowledge regarding the relationship between the Central Nervous System and the gastrointestinal tract, which could help to develop new preventive and treatment protocols.

    更新日期:2019-12-19
  • Adult hippocampal neurogenesis and antidepressants effects
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-11-27
    Barbara Planchez, Alexandre Surget, Catherine Belzung

    The hippocampus is particularly involved in cognitive processes and is a key regulator of stress responses and emotions. Therefore, the role of adult-born neurons in this region has become a crucial field of research in order to understand mood and stress disorders, such as major depression. Many studies have characterized the role of these neurons in cognition, mood regulation and antidepressant actions. Nevertheless, the precise mechanisms underpinning their antidepressant effects remain unclear. In this review, we first discuss the effects of stress and antidepressant treatments on adult neurogenesis, and subsequently, the functional roles of adult-born neurons and the mechanisms underlying their antidepressant action. Some studies have shown that adult-born neurons could affect overall hippocampal activity and thus normalize it under depression, which could restore neuronal pathways underlying antidepressant effects.

    更新日期:2019-11-28
  • Neuroimmune and epigenetic mechanisms underlying persistent loss of hippocampal neurogenesis following adolescent intermittent ethanol exposure
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-11-25
    Victoria Macht, Fulton T Crews, Ryan P Vetreno

    Alcohol abuse and binge drinking are common during adolescence — a maturational period characterized by heightened hippocampal neuroplasticity and neurogenesis. Preclinical rodent models of adolescent binge drinking (i.e., adolescent intermittent ethanol [AIE]) find unique vulnerability of adolescent hippocampal neurogenesis with reductions persisting into adulthood after ethanol cessation. Recent discoveries implicate increased neuroimmune signaling and decreased neurotrophic support through epigenetic mechanisms in the persistent AIE-induced loss of neurogenesis. Importantly, interventions aimed at rectifying the increased neuroimmune signaling and neurotrophic-epigenetic modifications through physical activity, anti-inflammatory drugs, and histone deacetylase inhibitors protect and recover the loss of neurogenesis and cognitive deficits. The mechanisms underlying the persistent AIE-induced loss of adult hippocampal neurogenesis could contribute to broader neurodegeneration, loss of hippocampal neuroplasticity, and cognitive dysfunction.

    更新日期:2019-11-26
  • Rejuvenating subventricular zone neurogenesis in the aging brain
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-11-19
    Ronald R Cutler, Erzsebet Kokovay

    Neural stem cells exist in specialized regions of the brain and have the capacity to give rise to neurons and glia over the lifespan. The process of giving rise to new neurons, also known as neurogenesis, is thought to be important in cognition and certain types of brain repair. However, during aging, neural stem cell number and function is reduced resulting in fewer new neurons and declines in learning, memory and repair. Recently, research has approached this problem through the lens of rejuvenation that now has produced several strategies, from dietary to pharmacological interventions, to restore functional neurogenesis that resembles the youthful brain. Here, we outline aging in the subventricular zone neurogenic niche, review the multiple modalities of rejuvenation strategies, and propose next steps for future studies to approach translational outcomes.

    更新日期:2019-11-20
  • The role of gut microbiota in obesity, diabetes mellitus, and effect of metformin: new insights into old diseases
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-04-20
    Alessia Pascale, Nicoletta Marchesi, Stefano Govoni, Adriana Coppola, Carmine Gazzaruso

    There is a recent growing evidence that abnormalities in the microbiota composition can have a major role in the development of obesity and diabetes and that some actions of metformin may be mediated by gut bacteria. Several mechanisms have been found. A reduced microbial diversity is associated to inflammation, insulin-resistance, and adiposity. In particular, a rise in the Firmicutes/Bacteroidetes ratio is related to a low-grade inflammation and to an increased capability of harvesting energy from food. Interestingly, high-fat-diet favors the growth of bacteria capable of extracting more energy from food. Changes in some metabolites, such as short-chain fatty acids (SCFAs), produced by gut microbiota, and decreased amounts of the Akkermansia muciniphila are associated with the presence of type 2 diabetes. Among the mechanisms by which metformin acts on glucose metabolism and on the cardiovascular risk, some of them are due to positive effects on gut microbiota. A shift toward positive SCFAs produced by bacteria, an increase in some bacterial strains, including A. muciniphila, and some actions on bile acids mediated by microbiota have been described. All these recent advances have been reported and discussed.

    更新日期:2019-11-18
  • Germ-free animal experiments in the gut microbiota studies
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-04-30
    Tayfun Uzbay

    Gut microbiota has a crucial role in the maintenance of health. Increasing evidence suggests that changes or disturbances in gut microbiota may be associated with various diseases. Therefore, preclinical and clinical studies related to gut microbiota are becoming increasingly important. Germ-free animal experimentation is one of the most important in vivo experimental models for preclinical studies on gut microbiota interactions. It represents a model to study effect of probiotic research and other experimental animal studies requiring careful control of outside contaminants that can affect the trial. Germ-free animals have defected immune systems, so they are used to model immune mediated metabolic, peripheral, and central diseases. In addition, gut–brain axis studies have recently increased. This minireview provides current information on this model and discusses the validity of its use in gut microbiota studies.

    更新日期:2019-11-18
  • The gut microbiome and pharmacology: a prescription for therapeutic targeting of the gut–brain axis
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-05-10
    Pauline M.B. Leprun, Gerard Clarke

    New frontiers for host-microbe interactions continue to emerge as our knowledge of the adult gut microbiome in health and disease is continually supplemented and improved. Alterations in the gut microbiota composition in irritable bowel syndrome (IBS) are now linked to symptom severity while population-based evidence linking gut microbiome signatures to depression is an important new landmark. The effects of drugs on gut microbiome composition are also becoming clearer. Meanwhile, preclinical studies have delineated the influence of the gut microbiome at a structural and activity level in distinct brain regions. Bacterial metabolites, such as tryptamine, can activate specific receptors to impact gastrointestinal motility. These recent studies bring into focus the future implications for therapeutic targeting of the microbiome–gut–brain axis.

    更新日期:2019-11-18
  • Evolution of fecal microbiota transplantation in methodology and ethical issues
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-05-03
    Faming Zhang, Ting Zhang, Heming Zhu, Thomas J Borody

    Fecal microbiota transplantation (FMT), the core therapy for remodeling the gut microbiota with a long medical history, has gained great attention worldwide in recent years. Increasing studies have explored its indications, methodology, efficacy, safety, and ethics. Purified forms of FMT, using an automated method for the purification of fecal microbiota from stool, has become a reality. Colonic transendoscopic enteral tubing makes frequent FMT delivery into the whole colon feasible. This review focuses on the recent progress in laboratory preparation, updated clinical strategies, novel delivery methods, and ethical issues surrounding FMT in clinical studies.

    更新日期:2019-11-18
  • Fecal microbiota transplantation donation: the gift that keeps on giving
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-05-11
    Erica P Turse, Francis E Dailey, Yezaz A Ghouri, Veysel Tahan
    更新日期:2019-11-18
  • The dirty aspects of fecal microbiota transplantation: a review of its adverse effects and complications
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-05-16
    Francis E Dailey, Erica P Turse, Ebubekir Daglilar, Veysel Tahan
    更新日期:2019-11-18
  • Fecal microbiota transplantation as a new therapy: from Clostridioides difficile infection to inflammatory bowel disease, irritable bowel syndrome, and colon cancer
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-06-05
    Thomas J Borody, Guy D Eslick, Robert L Clancy

    Fecal microbiota transplantation (FMT) represents the most effective means of therapeutically manipulating the gastrointestinal microbiome. Originally employed as a treatment of last-resort in patients with life-threatening Clostridioides difficile infection (CDI), FMT gained widespread acceptance during the CDI epidemic, where it achieved resolution rates approaching 100%. Following our newfound appreciation for the role of the gut microbiome in both health and disease and owing to FMT’s unique mechanism/s of action, FMT is rapidly advancing as an effective treatment for a number of conditions in which the gastrointestinal microbiome is thought to play a role. We review the role of FMT from its beginnings in CDI to its expansion into inflammatory bowel disease, irritable bowel syndrome, and colon cancer.

    更新日期:2019-11-18
  • Autoimmunity in microbiome-mediated diseases and novel therapeutic approaches
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-05-24
    Cheolmin Shin, Yong-Ku Kim

    The microbiome mediates constant bidirectional communication with the host immune system in a delicate balance of inducing pathogenic infection or residing in the human body in a commensal state. Dysbiosis is a hallmark of several autoimmune and immune-mediated inflammatory diseases. Various pathways involved in microbiome-induced autoimmunity are activated when a genetic defect or microbial trigger is found in the inflammasome, neutrophil extracellular trap, or receptors for microbial sensitization in the innate immune system or when similar defects are present in T or B lymphocytes of the adaptive immune system. Regulating autoimmunity through microbiome modulation may be highly effective as a therapeutic intervention.

    更新日期:2019-11-18
  • 更新日期:2019-11-08
  • Recent advances in the non-invasive assessment of fibrosis using biomarkers.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-11-23
    Amanda L Tatler

    Fibrosis can occur in most organs and is characterised by excessive and progressive extracellular matrix deposition and destruction of normal tissue architecture and function. In many cases treatment options are limited. Fibrotic diseases are therefore associated with high morbidity and mortality. Tissue biopsies remain a key part of diagnosing fibrosis; however, due to their invasive nature, tissue biopsies are unsuitable for monitoring disease progression. In some cases, tissue biopsies carry an unacceptable risk of mortality to the patient. Furthermore, assessing fibrosis via tissue biopsy is severely limited by the heterogenetic nature of fibrotic diseases and suffers from both sampling bias and observer variation/bias. The search for less invasive methods of diagnosing and monitoring fibrosis has led to the identification of many new biomarkers, many of which can be measured in serum in a so-called 'liquid biopsy' or can be imaged using state-of-the-art imaging modalities. These approaches have the potential to dramatically improve the diagnosis and monitoring of disease, and improve the design of clinical trials in to novel fibrotic therapies. This review summarises some of the recent advances in identifying novel biomarkers to diagnose and monitor fibrosis non-invasively.

    更新日期:2019-11-01
  • Implementation of pre-clinical methodologies to study fibrosis and test anti-fibrotic therapy.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-11-16
    Fiona Oakley,Lucy M Gee,Neil S Sheerin,Lee A Borthwick

    Diseases where fibrosis plays a major role accounts for enormous morbidity and mortality and yet we have very little in our therapeutic arsenal despite decades of research and clinical trials. Our understanding of fibrosis biology is primarily built on data generated in conventional mono-culture or co-culture systems and in vivo model systems. While these approaches have undoubtedly enhanced our understanding of basic mechanisms, they have repeatedly failed to translate to clinical benefit. Recently, there had been a push to generate more physiologically relevant platforms to study fibrosis and identify new therapeutic targets. Here we review the state-of-the-art regarding the development and application of 3D complex cultures, bio-printing and precision cut slices to study pulmonary, hepatic and renal fibrosis.

    更新日期:2019-11-01
  • Advances in the epigenetics of fibroblast biology and fibrotic diseases.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-11-16
    Bürge Ulukan,Yasemin Sila Ozkaya,Müjdat Zeybel

    Fibroblasts have a central role in tissue fibrosis and fibrotic diseases. Fibroblast activation is regulated by several mechanisms including epigenetic modifications; histone modifications, DNA methylation and non-coding RNAs. Although research has significantly contributed to our basic understanding of fibrotic diseases over the last decade, cooperative activity of epigenetic mechanisms demonstrates the complexity of fibrogenesis. This review will summarise the latest epigenetic advances in fibroproliferative diseases. Current studies investigating biological implications of epigenetic modifiers, inhibitors of DNA methylation/histone modifying enzymes are promising. Given that ncRNA-based or CRISPR-based epigenetic-editing have shown therapeutic potential in the preclinical models; we consider epigenetic mechanisms represent a potential tool with clinical utility.

    更新日期:2019-11-01
  • Editorial overview: Fibrosis.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-11-09
    Lee Borthwick,Fiona Oakley

    更新日期:2019-11-01
  • Resolving intestinal fibrosis through regenerative medicine.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-11-07
    Renate Schwab,Rebecca Lim,Rimma Goldberg

    Crohn's Disease and Ulcerative Colitis, known collectively as Inflammatory Bowel Disease (IBD), are lifelong gastrointestinal disorders that commonly present at a young age and are increasing in incidence and prevalence. Fibrosis is a common and incurable complication of IBD. When fibrotic complications occur, patients often have to undergo disfiguring surgery. Thus, research has focused on regenerative therapies as a means to prevent and treat established fibrosis. Both cell and non-cell therapies (exosomes) have anti-fibrotic and anti-inflammatory properties. This review discusses these emerging therapeutics and their potential to treat intestinal fibrosis.

    更新日期:2019-11-01
  • Pathology and natural history of organ fibrosis.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-11-02
    Joaquim Majo,Barbara Mara Klinkhammer,Peter Boor,Dina Tiniakos

    Histopathological assessment of fibrosis focusing on morphological patterns provides important information for the management of patients with chronic diseases of the kidney, liver and the lung. This review summarizes key histopathological features of pulmonary, renal and hepatic fibrosis and discusses advances in the understanding of the pathogenesis of pulmonary fibrosis and pathogenetic insights with translational implications for renal fibrosis. The review also tackles new staging approaches based on liver fibrosis dynamics and evaluation of fibrosis regression, digital pathology and second harmonic generation microscopy methods for hepatic fibrosis assessment and critical appraisal of non-invasive tests for liver and renal fibrosis evaluation.

    更新日期:2019-11-01
  • Fibrosis and the intestinal microbiome; a focus on chronic liver disease.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-11-02
    Naiara Beraza

    The role of the microbiome in progression of liver disease is an exciting area of research that is advancing rapidly supported by the development of next-generation sequencing and bioinformatics tools that simultaneously identify the composition and function of the microbiome. Changes in the microbiome are associated with pathogenesis of chronic liver disease; specifically, changes in microbiome composition predict disease severity and specific microbial signatures can be used to distinguish between mild disease, advanced fibrosis and cirrhosis. Future work combining functional metagenomic analysis with preclinical mechanistic studies will be key to advancing our understanding of how the microbiome affects the pathogenesis of different chronic liver disease aetiologies and to identify personalised therapeutics based on modulation of the microbiome and its function.

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Improving therapy of severe infections through drug repurposing of synergistic combinations.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-08-28
    Yu-Shan Cheng,Peter R Williamson,Wei Zheng

    Infections from multidrug resistant (MDR) pathogens and emerging viruses present challenges for effective clinical treatments. Drug repurposing and combination screens may provide therapies at a fraction of the time and cost of traditional methods of drug development. Synergistic combinations of two or three known compounds can increase therapeutic efficacy and reduce concentrations required for individual drugs, in turn, reducing the risk of drug toxicity. Using libraries of approved drugs, traditionally non-antibiotic compounds identified in repurposing screens can quickly move into clinical trials, since safety profiles have been previously established. Herein we summarize recent advances in identifying synergistic drug combinations and the use of drug screens for personalized medicine treatments of infections caused by MDR pathogens and emerging viruses.

    更新日期:2019-11-01
  • The role of the endothelial glycocalyx in advanced age and cardiovascular disease.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-05-22
    Daniel R Machin,Tam Tt Phuong,Anthony J Donato

    The endothelial glycocalyx is a gel-like structure that is bound to the luminal surface of the vascular endothelium. At the interface between flowing blood and endothelial cells, the glycocalyx has several functions that are critical for the maintenance of a healthy vasculature, particularly in regard to the vascular endothelium. Within the vasculature, the glycocalyx modulates vascular resistance to maintain blood flow homogeneity in the microcirculation, mechanotransduces fluid shear stress to the endothelium, and buffers endothelial cells from plasma oxidants, cytokines, and circulating immune cells. In advanced age and cardiovascular disease (CVD), the glycocalyx is deteriorated. Moreover, glycocalyx deterioration may precede traditional measurements of age-related vascular dysfunction, such as impaired endothelium-dependent dilation and large artery stiffness, suggesting that a deteriorated glycocalyx could initiate age-related CVD pathology.

    更新日期:2019-11-01
  • Microfluidics for personalized drug screening of cancer.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-10-22
    Nishanth Venugopal Menon,Su Bin Lim,Chwee Teck Lim

    Resistance to targeted therapies is a major clinical challenge in cancer treatment. Despite technological advances, robust biomarkers or platforms predictive of treatment response are lacking owing to the inherent nature of complex genomic landscape of carcinoma. Nevertheless, recent efforts centred on performing direct drug screening on patient-derived cells through their ex vivo expansion and maintenance have enabled personalized stratification of treatment modalities. Microfluidics is one such technology that allows high-throughput drug screening through parallelization and automation using small-volume sample. In this review, we present recent microfluidic platforms that have been successfully applied for the maintenance and expansion of patient-derived tumor cells spanning diverse cancer types and sources (solid tumors or liquid biopsies (circulating tumor cells)) for personalized drug screening applications.

    更新日期:2019-11-01
  • The NIH microphysiological systems program: developing in vitro tools for safety and efficacy in drug development.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-10-18
    Danilo A Tagle

    Approximately 30% of drugs have failed in human clinical trials due to adverse reactions despite promising pre-clinical studies, and another 60% fail due to lack of efficacy. One of the major causes in the high attrition rate is the poor predictive value of current preclinical models used in drug development despite promising pre-clinical studies in 2-D cell culture and animal models. Microphysiological Systems or Tissue Chips are bioengineered microfluidic cell culture systems seeded with primary or stem cells that mimic the histoarchitecture, mechanics and physiological response of functional units of organs and organ systems. These platforms are useful tools for predictive toxicology and efficacy assessments of candidate therapeutics. Implementation of tissue chips in drug development requires effective partnerships with stakeholders, such as regulatory agencies, pharmaceutical companies, patient groups, and other government agencies. Tissue chips are also finding utility in studies in precision medicine, environmental exposures, reproduction and development, infectious diseases, microbiome and countermeasures agents.

    更新日期:2019-11-01
  • Focus on the essentials: tryptophan metabolism and the microbiome-gut-brain axis.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-10-15
    Cassandra Elise Gheorghe,Jason A Martin,Francisca Villalobos Manriquez,Timothy G Dinan,John F Cryan,Gerard Clarke

    The gut-brain axis is a bidirectional communication system between the central nervous system and the gastrointestinal tract, in which serotonin (5-HT) functions as a key neurotransmitter. Recent research has increasingly concentrated on tryptophan, the precursor to 5-HT and on the microbial regulation of tryptophan metabolism, with an emphasis on host-microbe control over kynurenine pathway metabolism and microbial-specific pathways that generate bioactive tryptophan metabolites. Here, we critically assess recent progress made towards a mechanistic understanding of the microbial regulation of tryptophan metabolism and microbiota-gut-brain axis homeostasis highlighting the role tryptophan metabolism plays in preclinical and clinical neuroscience and in the challenge to improve our understanding of how perturbed tryptophan metabolism contributes to stress-related psychiatric disorders.

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Rhythm on a chip: circadian entrainment in vitro is the next frontier in body-on-a chip technology.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-10-11
    Jean-Michel Fustin,Meina Li,Bryan Gao,Qianyu Chen,Tianhong Cheng,Alastair G Stewart

    Organoids, bioprinted mini-tissues and body-on-a-chip technologies are poised to transform the practice of preclinical pharmacology, with a view to achieving better predictive value. We review the need for further refinement in static and dynamic biomechanical aspects of such microenvironments. Further consideration of the developments required in perfusion systems to enable delivery of an appropriate soluble microenvironment are argued. We place particular emphasis on a major deficiency in these systems, being the absence or aberrant circadian behaviour of cells used in such settings, and consider the technical challenges that are needing to be met in order to achieve rhythm-on-a-chip.

    更新日期:2019-11-01
  • Microbial regulation of microRNA expression in the brain-gut axis.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-10-08
    Gerard M Moloney,Timothy G Dinan,Gerard Clarke,John F Cryan

    The gut microbiome facilitates a consistent transfer of information between the gut and the brain and microRNAs may now represent a key signalling molecule that facilitates this relationship. This review will firstly examine how these small non-coding RNAs influence the gut microbiome, and secondly how the microbiome, when disturbed, may influence miRNA expression in the brain. In addition, we will examine the consequence that microbiome-related changes in miRNA expression have on neurodevelopment, behaviour and cognition. We will also discuss novel data that suggests miRNAs contained in our diet may influence our immune system in a positive manner, offering a further potential pathway for treatment of disorders of the gut-brain axis that are influenced by the microbiome.

    更新日期:2019-11-01
  • Human pluripotent stem cells for the modelling of diseases of the retina and optic nerve: toward a retina in a dish.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-10-08
    Grace E Lidgerwood,Alex W Hewitt,Alice Pébay

    Human pluripotent stem cells can be differentiated into specific, relevant cell types of interest including the cells of the retina and optic nerve. These cells can then be used to study fundamental biology as well as disease modelling and subsequent screening of potential treatments. Many models of differentiation and modelling have relied on two-dimensional monocultures of specific cell types, which are not representative of the complexity of the human retina and optic nerve. Hence, more complex models of the human retina and optic nerve are required. Three-dimensional organoids and emerging cell culture methods may provide more physiologically relevant models to study developmental biology and pathology of the retina and optic nerve.

    更新日期:2019-11-01
  • Bacterial peptidoglycans as novel signaling molecules from microbiota to brain.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-09-27
    Giorgia Tosoni,Mirko Conti,Rochellys Diaz Heijtz

    Mounting evidence indicates that gut microbiota exerts a broad range of effects on host physiology and development beyond the gastrointestinal tract, including the modulation of brain development. However, the mechanisms mediating the interactions between the microbiota and the developing brain are still poorly understood. Pattern recognition receptors of the innate immune system that recognize microbial products, such as peptidoglycans have emerged as potential key regulators of gut microbiome-brain interactions. Peptidoglycan-sensing molecules are expressed in the placenta and brain during specific time windows of development. Moreover, peptidoglycans are ubiquitously present in circulation and can cross the blood brain barrier. This review brings together the current evidence supporting a broad function of peptidoglycans well beyond host's immunity, extending to neurodevelopment and behavior.

    更新日期:2019-11-01
  • Editorial overview: CNS diseases and the microbiome.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-09-25
    Rochellys Diaz Heijtz,Jonathan Swann

    更新日期:2019-11-01
  • Editorial overview: Anti-infectives 2019 volume.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-09-22
    Sergio Sánchez,Arnold L Demain

    更新日期:2019-11-01
  • Small talk: microbial metabolites involved in the signaling from microbiota to brain.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-09-17
    Giorgia Caspani,Jonathan Swann

    The wealth of biotransformational capabilities encoded in the microbiome expose the host to an array of bioactive xenobiotic products. Several of these metabolites participate in the communication between the gastrointestinal tract and the central nervous system and have potential to modulate central physiological and pathological processes. This biochemical interplay can occur through various direct and indirect mechanisms. These include binding to host receptors in the brain, stimulation of the vagus nerve in the gut, alteration of central neurotransmission, and modulation of neuroinflammation. Here, the potential for short chain fatty acids, bile acids, neurotransmitters and other bioactive products of the microbiome to participate in the gut-brain axis will be reviewed.

    更新日期:2019-11-01
  • On the origin of eating disorders: altered signaling between gut microbiota, adaptive immunity and the brain melanocortin system regulating feeding behavior.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-08-21
    Sergueï O Fetissov,Tomas Hökfelt

    Research in the field of gut microbiota - brain axis may contribute to clarifying the origin of anorexia nervosa and bulimia, the two principal forms of eating disorders (ED). The initial key findings in ED patients of plasma immunoglobulins (Ig) that react with α-melanocyte-stimulating hormone (α-MSH), a neuropeptide in the brain signaling satiety, have initiated further studies leading to the discovery of the origin of such autoantibodies and to the understanding their possible functional role. An anorexigenic bacterial protein Escherichia coli caseinolytic protease B was recently found to be responsible for the production of α-MSH-cross-reactive autoantibodies and this protein was also detected in human plasma. Another recent study revealed enhanced activation of appetite-regulating the melanocortin type 4 receptor by immune complexes withα-MSH. Taken together, these data serve to build a pathophysiological model of ED presented in this article.

    更新日期:2019-11-01
  • Bacterial cross-resistance to anti-infective compounds. Is it a real problem?
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-06-19
    Elizabete de Souza Cândido,Elizângela de Barros,Marlon Henrique Cardoso,Octávio Luiz Franco

    Bacterial resistance has been listed as one of the main threats to human health, leading to high mortality rates. Among the mechanisms involved in bacterial resistance proliferation and selection, we can cite cross-resistance, which occurs when resistance events to one anti-infective agent trigger resistance to other agents. Thus, considering the importance of cross-resistance evolution worldwide in the context of resistant bacterial infections, this minireview focused on the description of bacterial adaptation, including biofilm formation. Here, we explored the correlation between different anti-infective agents, including antibiotics, metal ions, biocides, and antimicrobial peptides in bacterial cross-resistance, also highlighting the most reported mechanisms of adaptation that accompany this resistance.

    更新日期:2019-11-01
  • Antibacterials in the pipeline and perspectives for the near future.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-06-15
    Ian M Gould,Chathuri Gunasekera,Ali Khan

    Antimicrobial resistance is a global threat to the management of infections in our patients. Sound stewardship of antibacterial agents at our disposal must be accompanied by a concerted effort to develop new agents to bolster our armamentarium. This review will cover the latest antibiotics that have come through the pipeline and the role they can play in the management of infections that are increasingly difficult to treat due to resistance mechanisms.

    更新日期:2019-11-01
  • Strategies for discovery of new molecular targets for anti-infective drugs.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-05-31
    Manuel F Varela,Sanath Kumar

    Multidrug resistant bacterial pathogens as causative agents of infectious disease are a primary public health concern. Clinical efficacy of antimicrobial chemotherapy toward bacterial infection has been compromised in cases where causative agents are resistant to multiple structurally distinct antimicrobial agents. Modification of extant antimicrobial agents that exploit conventional bacterial targets have been developed since the advent of the antimicrobial era. This approach, while successful in certain cases, nonetheless suffers overall from the costs of development and rapid emergence of bacterial variants with confounding resistances to modified agents. Thus, additional strategies toward discovery of new molecular targets have been developed based on bioinformatics analyses and comparative genomics. These and other strategies meant to identify new molecular targets represent promising avenues for reducing emergence of bacterial infections. This short review considers these strategies for discovery of new molecular targets within bacterial pathogens.

    更新日期:2019-11-01
  • The race between drug introduction and appearance of microbial resistance. Current balance and alternative approaches.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-05-29
    Esaú López-Jácome,Rafael Franco-Cendejas,Héctor Quezada,Rosario Morales-Espinosa,Israel Castillo-Juárez,Bertha González-Pedrajo,Ana María Fernández-Presas,Arturo Tovar-García,Vanesa Angarita-Zapata,Paula Licona-Limón,Mariano Martínez-Vázquez,Rodolfo García-Contreras

    As current levels of antimicrobial resistance are alarming, the World Health Organization urged the development of new antimicrobials to fight infections produced by multidrug resistant bacteria. Antibiotics impose severe selective pressure for the development of resistance, and currently bacteria resistant to all of them exist. In this review, we discuss the release and development of new antibacterial drugs and their properties as well as the current advances in the development of alternative approaches to combat bacterial infections, including the repurposing of drugs, anti-virulence therapies, the use of photosensitizers, phage therapy, and immunotherapies, with an emphasis on what is currently known about the possible development of bacterial resistance against them.

    更新日期:2019-11-01
  • Recent findings of molecules with anti-infective activity: screening of non-conventional sources.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-05-12
    Arnold L Demain,Brenda Gómez-Ortiz,Beatriz Ruiz-Villafán,Romina Rodríguez-Sanoja,Sergio Sánchez

    In recent years, the number of pathogenic microorganisms resistant to antibiotics has increased alarmingly. For the next 10-20 years, health organizations forecast high human mortality caused by these microorganisms. Therefore, the search for new anti-infectives is quite necessary and urgent. Traditionally, antibiotic-producing microorganisms have been isolated from common soil samples. However, this source seems to be exhausted considering the very few examples of antibiotic-producing microorganisms reported recently. In this review, non-conventional sources of anti-infective producing microorganisms are presented as a possible way to look for new and more effective compounds. These sources included arid soils, caves, areas with high temperatures (hot springs), high salinity or oceans and seas. Finally, other non-conventional sources of antibiotics reviewed are animal and invertebrate venoms, among others.

    更新日期:2019-11-01
  • Current and emerging therapies to combat persistent intracellular pathogens.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-05-06
    Philip Arandjelovic,Marcel Doerflinger,Marc Pellegrini

    Intracellular pathogens such as HIV, hepatitis B virus, and Mycobacterium tuberculosis are responsible for millions of deaths worldwide and represent major obstacles to global health. Current treatment options have improved patient outcomes and extended life-expectancy in many countries; however, challenges such as latency, drug-resistance, and inflammatory pathology have necessitated advancements in curative strategies which go beyond the traditional antimicrobial focus. This review highlights recent advances in host-directed therapies to eradicate intracellular pathogens or augment the endogenous immune response by targeting host cell pathways. The 'kick and kill' strategy for HIV latency, adjunct immunomodulatory compounds for tuberculosis, and pro-apoptotic small-molecule inhibitors in the case of chronic Hepatitis B are promising examples of host-directed therapies that signal a paradigm shift in treatment and management of chronic infectious disease.

    更新日期:2019-11-01
  • Phylogenies in ART: HIV reservoirs, HIV latency and drug resistance.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2019-04-29
    Alessandra Bandera,Andrea Gori,Mario Clerici,Manuela Sironi

    Combination antiretroviral therapy (ART) has significantly reduced the morbidity and mortality resulting from HIV infection. ART is, however, unable to eradicate HIV, which persists latently in several cell types and tissues. Phylogenetic analyses suggested that the proliferation of cells infected before ART initiation is mainly responsible for residual viremia, although controversy still exists. Conversely, it is widely accepted that drug resistance mutations (DRMs) do not appear during ART in patients with suppressed viral loads. Studies based on sequence clustering have in fact indicated that, at least in developed countries, HIV-infected ART-naive patients are the major source of drug-resistant viruses. Analysis of longitudinally sampled sequences have also shown that DRMs have variable fitness costs, which are strongly influenced by the viral genetic background.

    更新日期:2019-11-01
  • The proton-coupled folate transporter: physiological and pharmacological roles.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2014-01-03
    Rongbao Zhao,I David Goldman

    Recent studies have identified the proton-coupled folate transporter (PCFT) as the mechanism by which folates are absorbed across the apical brush-border membrane of the small intestine and across the basolateral membrane of the choroid plexus into the cerebrospinal fluid. Both processes are defective when there are loss-of-function mutations in this gene as occurs in the autosomal recessive disorder hereditary folate malabsorption. Because this transporter functions optimally at low pH, antifolates are being developed that are highly specific for PCFT in order to achieve selective delivery to malignant cells within the acidic environment of solid tumors. PCFT has a spectrum of affinities for folates and antifolates that narrows and increases at low pH. Residues have been identified that play a role in folate and proton binding, proton coupling, and oscillation of the carrier between its conformational states.

    更新日期:2019-11-01
  • Targeting for cardioplegia: arresting agents and their safety.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2009-06-06
    Hazem B Fallouh,Jonathan C Kentish,David J Chambers

    Elective temporary cardiac arrest (cardioplegia) is often required during cardiac surgery. In the 1970 s, the development of hyperkalaemic cardioplegic solutions revolutionised cardiac surgery by offering effective chemically-induced cardiac arrest and myocardial protection during global ischaemia. Despite remaining the most widely-used cardioplegic technique, hyperkalaemia can have detrimental effects due to the Na and Ca loading of the cardiac cell induced by depolarisation of the cell membrane. Efforts over the last two decades to establish better cardioplegic agents have mainly remained limited to animal experiments. The failure of these approaches to progress to clinical trials may be due to a lack of clear criteria that a cardioplegic agent should meet at a cellular level and, more importantly, at a system level. In this review we attempt to define the criteria for the optimal cardioplegic agent. We also assess the suitability and clinical potential of previously-studied cardioplegic agents and suggest cellular targets, particularly those involved in cardiac excitation-contraction coupling, that may prove to be attractive options for the development of new cardioplegic drugs. Finally, we propose a multicellular target approach using a combination of pharmacological agents in order to offer better cardioplegic solutions.

    更新日期:2019-11-01
  • Vasopressin receptor antagonists in heart failure.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2003-12-04
    Marc Thibonnier

    There is ample evidence that arginine vasopressin (AVP) is a component of the neurohormonal response to congestive heart failure (CHF). Furthermore, AVP might play a role in the development, progression and worsening of CHF. Because of the need for further improvement in the treatment of CHF, randomized clinical trials were conducted to assess the efficacy and safety of non-peptide AVP receptor antagonists in patients with CHF. In pivotal trials of three non-peptide AVP receptor antagonists, these compounds improved the fluid status, osmotic balance and hemodynamics of patients with CHF. These studies support the approval of this class of agents for the symptomatic treatment of CHF, but long-term studies are required to demonstrate their role in the outcome and quality of life of these patients.

    更新日期:2019-11-01
  • Therapy for polycystic ovarian syndrome.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2003-12-04
    Alex Y Wei,Elizabeth A Pritts

    Polycystic ovarian syndrome is the most common endocrine disorder in women of reproductive age. Women with this disorder exhibit an array of disorders, including oligo-ovulation, hyperandrogenism, obesity, hyperlipidemia, infertility and insulin resistance. Of the sequelae that women experience, insulin resistance is associated with the most profound long-term morbidity. Initially, treatment regimens targeted specific symptomatology in these women, such as oligomenorrhea or hirsutism. With the discovery of the common association between insulin resistance and polycystic ovarian syndrome, however, we are able to utilize a new class of systemically targeted drugs that work on many of the symptoms found in these women.

    更新日期:2019-11-01
  • Medical treatment in acromegaly.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2003-12-04
    Angela N Paisley,Peter J Trainer

    Acromegaly is a rare disabling disorder that results in premature death. The excess mortality and morbidity are the result of prolonged elevation of growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels, and vigorous control of these improves well-being and restores life expectancy to normal. Recognition of the benefits of treatment has emphasised the need for optimal control of the GH/IGF-I axis. Transsphenoidal surgery is first-line therapy in the majority of patients; however, as most tumours are macroadenomas, cure rates are low. The role of radiotherapy is evolving and, although extremely effective at controlling tumour growth, it can take up to 15 years to control GH & IGF-I levels. In the interim, medical therapy is necessary. Dopamine agonists are inexpensive oral agents but, although most patients experience some benefit, GH and IGF-I levels are only normalised in around 35-40% of patients, and side effects are common. Somatostatin analogues are the gold standard of medical treatment. They can induce tumour shrinkage in a proportion of patients and can normalise the GH/IGF-I axis (at best) in approximately 65% of individuals; however, this leaves a significant cohort uncontrolled. The advent of the GH receptor antagonist pegvisomant provides the potential for IGF-I to be normalised in virtually every patient, but this novel form of therapy, which does not act on the pituitary, also raises many questions.

    更新日期:2019-11-01
  • Status and future direction of male contraceptive development.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2003-12-04
    C Richard Lyttle,Gregory S Kopf

    Control of fertility constitutes a global health issue, as overpopulation and unintended pregnancy have both major personal and societal impact. Although the contraceptive revolution in the 1960s following the development of hormonal-based oral contraceptives for women has had a major impact on societal dynamics in several cultures, little product innovation has occurred since then. One solution to this global health issue lies in the development of new and innovative contraceptives for both women and men, the goal of which is to provide a range of options for people at all stages and walks of life. Currently, three options for male-based contraception exist (i.e. withdrawal, condoms and vasectomy), and these are acknowledged as woefully inadequate. Introduction of new forms of male contraception based on both hormonal and non-hormonal paradigms are wanted and needed; this need is now becoming recognized by both the public and private sectors. New and innovative products will come from our knowledge of the unique physiology and genetics of reproduction, as well as by exploiting existing and future genomics, proteomics and protein network platforms.

    更新日期:2019-11-01
  • Gonadotropin-releasing hormone antagonists.
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2003-12-03
    Karen L Herbst

    Hypothalamic gonadotropin-releasing hormone (GnRH) is a decapeptide that stimulates pituitary synthesis and secretion of gonadotropins and, therefore, gonadal hormones. GnRH antagonists, of which thousands have been formulated, inhibit the hormone from binding to its receptor, inducing a pharmacological hypophysectomy. Peptide derivations of GnRH and non-peptide compounds are both in clinical trials or approved for assisted reproduction. As these compounds reach the market, the use of antagonists might expand to treatment of other hormonally dependent diseases, hormonal male contraception and growth inhibition of extra-pituitary cancer cells expressing GnRH receptors.

    更新日期:2019-11-01
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