Journal: British journal of pharmacology
The human distal gut is home to a rich and dense microbial community with representatives of all three domains of life which are intricately connected with our physiology and health. The combined genomes of these microbes, collectively called the human microbiome, vastly expand the metabolic capacities of our own genome, allowing us to break down and extract energy from dietary compounds that human enzymes cannot digest. In addition, the variable composition of these communities and their biotransformations might explain inter-individual differences in toxicities, tolerances, and efficacies for certain drugs. Recent advances in sequencing technologies and bioinformatics have provided exciting new insights into the genomes of our microbial symbionts, their functional capacities, and the interactions between these microbes and their human host. This review summarizes the metabolic conversions of dietary components and pharmaceuticals that take place in the human distal gut, as well as their implications for human health.
Phytoestrogens are plant-derived dietary compounds with structural similarity to 17-β-estradiol (E2), the primary female sex hormone. This structural similarity to E2 enables phytoestrogens to cause (anti)estrogenic effects by binding to the estrogen receptors. The aim of the present review is to present a state-of-the-art overview of the the potential health effects of dietary phytoestrogens. Various beneficial health effects have been ascribed to phytoestrogens, such as a lowered risk on menopausal symptoms like hot flushes and osteoporosis, lowered risks on cardiovascular disease, obesity, metabolic syndrome and type 2 diabetes, brain function disorders, breast cancer, prostate cancer, bowel cancer and other cancers. In contrast to these beneficial health claims, the (anti)estrogenic properties of phytoestrogens have also raised concerns since they might act as endocrine disruptors, indicating a potential to cause adverse health effects. The literature overview presented in this paper illustrates that several potential health benefits of phytoestrogens have been reported but that, given the data on potential adverse health effects, the current evidence on these beneficial health effects is not so obvious that they clearly outweigh the possible health risks. Furthermore, the currently available data are not sufficient to support a more refined (semi) quantitative risk-benefit analysis. This implies that a definite conclusion on possible beneficial health effects of phytoestrogens cannot be made.
In 2014, drug overdose surpassed automobile accidents as the number one cause of accidental death for the first time in US history. The overdose epidemic is largely driven by opioids, and genuine prescription opioid analgesics play the biggest role in this phenomenon. Despite advancements in abuse deterrent formulations, prescription drug monitoring programs, and clinical assessments for the detection of abuse potential, drug overdoses continue to escalate. The CDC has recently issued new guidelines for opioid prescription, yet even these recommendations have their shortcomings. Furthermore, undertreated pain in patients with comorbid substance use disorder poses a major clinical challenge, particularly for patients on opioid replacement therapy. Despite the seemingly obvious interaction between the presence of pain and the abuse of pain-relieving opioids, there is surprisingly little mechanistic data to further our understanding of this vitally important topic. The need for novel pain interventions that minimize abuse liability is critical. Without a fundamental characterization of pain neurobiology, and the interaction between chronic pain and the brain’s reward system, we are unlikely to make progress in the alleviation of the opioid epidemic.
Infectious diseases account for nearly one fifth of the worldwide death toll every year. Continuous increase of drug-resistant pathogens is a big challenge for treatment of infectious diseases. In addition, emerging outbreaks of infections and new pathogens are potential threats to public health. Lack of effective treatments for drug-resistant bacteria and recent outbreaks of Ebola and Zika viral infections have become a global public health concern. The number of newly approved antibiotics has decreased significantly in the last two decades compared to previous decades. Inversely paralleled with this, is an increase in the number of trend of drug-resistant bacteria. To counter these threats and challenges, new strategies and technology platforms are critically needed. Drug repurposing has emerged as an alternative approach for rapid identification of effective therapeutics to treat the infectious diseases. For treatment of severe infections, synergistic drug combination using approved drugs identified from drug repurposing screens is a useful option which may overcome the problem of weak activity of individual drugs. Collaborative efforts including government, academic researchers and private drug industry can facilitate the translational research to produce more effective new therapeutics such as narrow spectrum antibiotics against drug-resistant bacteria for these global challenges.
Atopic dermatitis (AD) is a multifactorial skin disease with complex interactions of innate and adaptive immune responses based on a genetic, pharmacological, and psychological predisposition. There are several treatment approaches for AD, including topical glucocorticosteroids, emollients, phototherapies, calcineurin inhibitors, and immunosuppressants, such as cyclosporine A. These therapies reduce inflammation, but they also cause various side effects. Therefore, it is necessary to develop new therapeutic approaches for AD treatment without side effects. There are several studies on natural materials or toxins, such as herbs, ginseng extract, and snake venom, for AD treatment. However, bee venom (BV) and melittin (Mel)-mediated AD treatment has rarely been studied.
Opioid addiction has devastating health and socio-economic consequences and current pharmacotherapy is limited and often accompanied by side effects, thus novel treatment is warranted. Traditionally, the neurohypophyseal peptide oxytocin (OT) is known for its effects in mediating reward, social affiliation/bonding and stress, as well as learning and memory. There is now strong evidence that oxytocin is a possible candidate for the treatment of drug addiction and depression-addiction co-morbidities. This review summarizes and critically discusses the preclinical evidence surrounding the consequences of pharmacological manipulation of the oxytocinergic system on opioid addiction-related processes, as well as the effects of opioids on the OT system at different stages of the addiction cycle. The mechanisms underlying the effects of OT in opioid addiction, including oxytocins' interaction with the monoaminergic, glutamatergic, opioidergic systems and its effect on the amygdala, the hypothalamic-pituitary-adrenal axis and on memory consolidation of traumatic memories are also reviewed. Moreover, we review clinical evidence on the effects of intranasal OT administration on opioid-dependent individuals and discuss the therapeutic potential along with the limitations that OT-based pharmacotherapies manifest. Review of these studies clearly indicates that the oxytocin system is profoundly affected by opioid use and abstinence and points towards the oxytocin system as an important target for developing pharmacotherapies for the treatment of opioid addiction and co-existing affective disorders, and thereby prevention of relapse. Therefore, clinical studies assessing the efficacy of OT-based pharmacotherapies in opioid addiction are warranted.
Because tumor necrosis factors (TNFs) are major mediators of inflammation and inflammation-related diseases, the United States Food and Drug Administration (FDA) has approved blockers of the cytokine, TNF-α, which include chimeric TNF antibody (Infliximab), humanized TNF-α antibody (Humira), and soluble TNF receptor-II (Enbrel). TNF blockers are now being used for the treatment of osteoarthritis, inflammatory bowel disease, psoriasis, and ankylosis at a total cumulative market value of more than $20 billion/year. Besides being expensive ($15,000-20,000/person/year), these drugs must be injected and have enough adverse effects to be given a black label warning by the FDA. In the current report, we describe an alternative, curcumin (diferuloylmethane), a component of turmeric (Curcuma longa) that is very inexpensive, orally bioavailable, and highly safe in humans, yet can block TNF-α action and production in in vitro models, in animal models, and in humans. In addition, we provide evidence for curcumin’s activities against all of the diseases for which TNF blockers are being used. Mechanisms by which curcumin inhibits the production and the cell signaling pathways activated by this cytokine are also discussed. With health care costs and safety being major issues today, this golden spice may help provide the solution.
It has been suggested that the non-psychoactive phytocannabinoid cannabidiol (CBD) can impact the pharmacological effects of delta-9-tetrahydrocannabinol (THC). We tested the hypothesis that CBD and THC would significantly mitigate mechanical sensitivity in a mouse model of paclitaxel-induced neuropathic pain, and that CBD+THC combinations would produce synergistic effects. We also tested the hypothesis that CBD would attenuate oxaliplatin- and vincristine- induced mechanical sensitivity.
The present study assessed the effects of cilostazol on LPS-stimulated TLR4 signal pathways in synovial macrophages from patients with rheumatoid arthritis (RA). These effects were confirmed in collagen-induced arthritis (CIA) in mice.
The trace amine-associated receptor (Taar) family displays high species- and subtype-specific pharmacology. Several trace amines such as β-phenylethylamine (β-PEA), p-tyramine and tryptamine are agonists at TA(1) but poorly activate rat and mouse Taar4.