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International Journal of Molecular... Mar 2023Neuropathic pain (NP) refers to pain caused by primary or secondary damage or dysfunction of the peripheral or central nervous system, which seriously affects the... (Review)
Review
Neuropathic pain (NP) refers to pain caused by primary or secondary damage or dysfunction of the peripheral or central nervous system, which seriously affects the physical and mental health of 7-10% of the general population. The etiology and pathogenesis of NP are complex; as such, NP has been a hot topic in clinical medicine and basic research for a long time, with researchers aiming to find a cure by studying it. Opioids are the most commonly used painkillers in clinical practice but are regarded as third-line drugs for NP in various guidelines due to the low efficacy caused by the imbalance of opioid receptor internalization and their possible side effects. Therefore, this literature review aims to evaluate the role of the downregulation of opioid receptors in the development of NP from the perspective of dorsal root ganglion, spinal cord, and supraspinal regions. We also discuss the reasons for the poor efficacy of opioids, given the commonness of opioid tolerance caused by NP and/or repeated opioid treatments, an angle that has received little attention to date; in-depth understanding might provide a new method for the treatment of NP.
Topics: Humans; Analgesics, Opioid; Receptors, Opioid; Down-Regulation; Drug Tolerance; Neuralgia
PubMed: 36983055
DOI: 10.3390/ijms24065981 -
Proceedings of the National Academy of... Feb 2023Tuberculosis treatment requires months-long combination chemotherapy with multiple drugs, with shorter treatments leading to relapses. A major impediment to shortening...
Tuberculosis treatment requires months-long combination chemotherapy with multiple drugs, with shorter treatments leading to relapses. A major impediment to shortening treatment is that becomes tolerant to the administered drugs, starting early after infection and within days of infecting macrophages. Multiple lines of evidence suggest that macrophage-induced drug tolerance is mediated by mycobacterial drug efflux pumps. Here, using assays to directly measure drug efflux, we find that transports the first-line antitubercular drug rifampicin through a proton gradient-dependent mechanism. We show that verapamil, a known efflux pump inhibitor, which inhibits macrophage-induced rifampicin tolerance, also inhibits rifampicin efflux. As with macrophage-induced tolerance, the calcium channel-inhibiting property of verapamil is not required for its inhibition of rifampicin efflux. By testing verapamil analogs, we show that verapamil directly inhibits drug efflux pumps through its human P-glycoprotein (PGP)-like inhibitory activity. Screening commonly used drugs with incidental PGP inhibitory activity, we find many inhibit rifampicin efflux, including the proton pump inhibitors (PPIs) such as omeprazole. Like verapamil, the PPIs inhibit macrophage-induced rifampicin tolerance as well as intramacrophage growth, which has also been linked to mycobacterial efflux pump activity. Our assays provide a facile screening platform for efflux pump inhibitors that inhibit in vivo drug tolerance and growth.
Topics: Humans; Mycobacterium tuberculosis; Rifampin; Proton Pump Inhibitors; Antitubercular Agents; Verapamil; Macrophages; Tuberculosis; Drug Tolerance; Bacterial Proteins; Microbial Sensitivity Tests
PubMed: 36763530
DOI: 10.1073/pnas.2215512120 -
Annual Review of Microbiology Sep 2019Persisters are nongrowing, transiently antibiotic-tolerant bacteria within a clonal population of otherwise susceptible cells. Their formation is triggered by... (Review)
Review
Persisters are nongrowing, transiently antibiotic-tolerant bacteria within a clonal population of otherwise susceptible cells. Their formation is triggered by environmental cues and involves the main bacterial stress response pathways that allow persisters to survive many harsh conditions, including antibiotic exposure. During infection, bacterial pathogens are exposed to a vast array of stresses in the host and form nongrowing persisters that survive both antibiotics and host immune responses, thereby most likely contributing to the relapse of many infections. While antibiotic persisters have been extensively studied over the last decade, the bulk of the work has focused on how these bacteria survive exposure to drugs in vitro. The ability of persisters to survive their interaction with a host is important yet underinvestigated. In order to tackle the problem of persistence of infections that contribute to the worldwide antibiotic resistance crisis, efforts should be made by scientific communities to understand and merge these two fields of research: antibiotic persisters and host-pathogen interactions. Here we give an overview of the history of the field of antibiotic persistence, report evidence for the importance of persisters in infection, and highlight studies that bridge the two areas.
Topics: Bacteria; Bacterial Infections; Drug Tolerance; Host-Pathogen Interactions; Microbial Viability; Stress, Physiological
PubMed: 31500532
DOI: 10.1146/annurev-micro-020518-115650 -
Microbiology Spectrum Dec 2014The survival capacity of microorganisms in a contaminated environment is limited by the concentration and/or toxicity of the pollutant. Through evolutionary processes,... (Review)
Review
The survival capacity of microorganisms in a contaminated environment is limited by the concentration and/or toxicity of the pollutant. Through evolutionary processes, some bacteria have developed or acquired mechanisms to cope with the deleterious effects of toxic compounds, a phenomenon known as tolerance. Common mechanisms of tolerance include the extrusion of contaminants to the outer media and, when concentrations of pollutants are low, the degradation of the toxic compound. For both of these approaches, plasmids that encode genes for the degradation of contaminants such as toluene, naphthalene, phenol, nitrobenzene, and triazine or are involved in tolerance toward organic solvents and heavy metals, play an important role in the evolution and dissemination of these catabolic pathways and efflux pumps. Environmental plasmids are often conjugative and can transfer their genes between different strains; furthermore, many catabolic or efflux pump genes are often associated with transposable elements, making them one of the major players in bacterial evolution. In this review, we will briefly describe catabolic and tolerance plasmids and advances in the knowledge and biotechnological applications of these plasmids.
Topics: Bacteria; Biological Transport; Drug Tolerance; Environmental Pollutants; Hydrocarbons; Metabolic Networks and Pathways; Metals, Heavy; Plasmids
PubMed: 26104447
DOI: 10.1128/microbiolspec.PLAS-0013-2013 -
BMJ Case Reports Apr 2021A 57-year-old woman presented with a 1-year history of major depressive disorder. She was started on venlafaxine XR 75 mg orally daily and a few days later developed...
A 57-year-old woman presented with a 1-year history of major depressive disorder. She was started on venlafaxine XR 75 mg orally daily and a few days later developed severe dysosmia to foods she used to enjoy. She never had previous problems with smell or taste. At her 1-month follow-up, her depressive symptoms had improved, but she reported persistent dysosmia and was found to have associated weight loss due to decreased oral intake. She was advised to switch medications, but due to financial constraints she continued taking the same dose. At follow-up 48 days later, she reported complete resolution of her dysosmia and was eating normally again, but she had persistence of some depressive symptoms so her dose was gradually increased to venlafaxine XR 225 mg orally daily until her depressive symptoms and postmenopausal hot flashes were well controlled. There were no changes with continued use over the following 8 years.
Topics: Depressive Disorder, Major; Drug Tolerance; Female; Humans; Middle Aged; Olfaction Disorders; Venlafaxine Hydrochloride
PubMed: 33853817
DOI: 10.1136/bcr-2020-240547 -
International Immunopharmacology Dec 2023Opioids are widely used in treating patients with acute and chronic pain; however, this class of drugs is also commonly abused. Opioid use disorder and associated... (Review)
Review
Opioids are widely used in treating patients with acute and chronic pain; however, this class of drugs is also commonly abused. Opioid use disorder and associated overdoses are becoming more prevalent as the opioid crisis continues. Chronic opioid use is associated with tolerance, which decreases the efficacy of opioids over time, but also puts individuals at risk of fatal overdoses. Therefore, it is essential to identify strategies to reduce opioid tolerance in those that use these agents. The gut microbiome has been found to play a critical role in opioid tolerance, with opioids causing dysbiosis of the gut, and changes in the gut microbiome impacting opioid tolerance. These changes in turn have a detrimental effect on the gut microbiome, creating a positive feedback cycle. We review the bidirectional relationship between the gut microbiome and opioid tolerance, discuss the role of modulation of the gut microbiome as a potential therapeutic option in opioid-induced gut dysbiosis, and suggest opportunities for further research and clinical interventions.
Topics: Humans; Analgesics, Opioid; Gastrointestinal Microbiome; Dysbiosis; Drug Tolerance; Opioid-Related Disorders
PubMed: 37918085
DOI: 10.1016/j.intimp.2023.111142 -
Journal of Analytical Toxicology Oct 2020The historical practice of brewing poppy tea for its opioid-like effects is reoccurring with modern-day substance users. We present four postmortem cases with toxicology...
The historical practice of brewing poppy tea for its opioid-like effects is reoccurring with modern-day substance users. We present four postmortem cases with toxicology results that serve as case studies for the potential hazards of poppy tea ingestion. There is limited information regarding the risks of this practice due to the variability of the morphine content of the opium exuded from the plant. While internet tea recipes offer guidance, differences in poppy cultivation, washing, and infusing time are some of the reasons why the beverage may contain inconsistent and clinically significant alkaloid concentrations for each preparation. Variability in opioid tolerance along with additional drugs taken will impact the overall degree of toxicity experienced from the opiates in the tea. Advancements in the genetic modification of the poppy plant could greatly alter the ratio of alkaloids seen in biological fluids and will be highly dependent on the source of the poppy product. The blood concentrations of free morphine and free codeine in cases 1-3 where the toxicity from the tea was considered the primary cause of death were 0.94 and 0.11 mg/L, 0.62 and 0.034 mg/L, and 0.16 and 0.010 mg/L, respectively. The urine concentrations of morphine and codeine were 13 and 0.94 mg/L in case 1 and 16 and 1.6 mg/L in case 2, respectively. The opium alkaloids thebaine and laudanosine were identified qualitatively by our routine organic base/neutral drug detection procedure.
Topics: Analgesics, Opioid; Drug Overdose; Drug Tolerance; Humans; Morphine; Papaver; Plant Extracts; Teas, Herbal
PubMed: 33043985
DOI: 10.1093/jat/bkaa093 -
Proceedings of the National Academy of... Jul 2019Understanding the evolution of microorganisms under antibiotic treatments is a burning issue. Typically, several resistance mutations can accumulate under antibiotic...
Understanding the evolution of microorganisms under antibiotic treatments is a burning issue. Typically, several resistance mutations can accumulate under antibiotic treatment, and the way in which resistance mutations interact, i.e., epistasis, has been extensively studied. We recently showed that the evolution of antibiotic resistance in is facilitated by the early appearance of tolerance mutations. In contrast to resistance, which reduces the effectiveness of the drug concentration, tolerance increases resilience to antibiotic treatment duration in a nonspecific way, for example when bacteria transiently arrest their growth. Both result in increased survival under antibiotics, but the interaction between resistance and tolerance mutations has not been studied. Here, we extend our analysis to include the evolution of a different type of tolerance and a different antibiotic class and measure experimentally the epistasis between tolerance and resistance mutations. We derive the expected model for the effect of tolerance and resistance mutations on the dynamics of survival under antibiotic treatment. We find that the interaction between resistance and tolerance mutations is synergistic in strains evolved under intermittent antibiotic treatment. We extend our analysis to mutations that result in antibiotic persistence, i.e., to tolerance that is conferred only on a subpopulation of cells. We show that even when this population heterogeneity is included in our analysis, a synergistic interaction between antibiotic persistence and resistance mutations remains. We expect our general framework for the epistasis in killing conditions to be relevant for other systems as well, such as bacteria exposed to phages or cancer cells under treatment.
Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Drug Tolerance; Epistasis, Genetic; Escherichia coli; Evolution, Molecular; Gene Expression Regulation, Bacterial; Microbial Sensitivity Tests; Models, Genetic; Mutation
PubMed: 31262806
DOI: 10.1073/pnas.1906169116 -
Pesticide Biochemistry and Physiology May 2015A series of common/shared point mutations in acetylcholinesterase (AChE) confers resistance to organophosphorus and carbamate insecticides in most arthropod pests.... (Review)
Review
A series of common/shared point mutations in acetylcholinesterase (AChE) confers resistance to organophosphorus and carbamate insecticides in most arthropod pests. However, the mutations associated with reduced sensitivity to insecticides usually results in the reduction of catalytic efficiency and leads to a fitness disadvantage. To compensate for the reduced catalytic activity, overexpression of neuronal AChE appears to be necessary, which is achieved by a relatively recent duplication of the AChE gene (ace) as observed in the two-spotted spider mite and other insects. Unlike the cases with overexpression of neuronal AChE, the extensive generation of soluble AChE is observed in some insects either from a distinct non-neuronal ace locus or from a single ace locus via alternative splicing. The production of soluble AChE in the fruit fly is induced by chemical stress. Soluble AChE acts as a potential bioscavenger and provides tolerance to xenobiotics, suggesting its role in chemical adaptation during evolution.
Topics: Acetylcholinesterase; Adaptation, Physiological; Animals; Drug Tolerance; Insect Proteins; Insecta; Insecticide Resistance; Mutation
PubMed: 25987229
DOI: 10.1016/j.pestbp.2014.11.004 -
Journal of Medicinal Chemistry Sep 2019Bacteria utilize multiple mechanisms that enable them to gain or acquire resistance to antibiotic therapies during the treatment of infections. In addition, bacteria... (Review)
Review
Bacteria utilize multiple mechanisms that enable them to gain or acquire resistance to antibiotic therapies during the treatment of infections. In addition, bacteria form biofilms which are surface-attached communities of enriched populations containing persister cells encased within a protective extracellular matrix of biomolecules, leading to chronic and recurring antibiotic-tolerant infections. Antibiotic resistance and tolerance are major global problems that require innovative therapeutic strategies to address the challenges associated with pathogenic bacteria. Historically, natural products have played a critical role in bringing new therapies to the clinic to treat life-threatening bacterial infections. This Perspective provides an overview of antibiotic resistance and tolerance and highlights recent advances (chemistry, biology, drug discovery, and development) from various research programs involved in the discovery of new antibacterial agents inspired by a diverse series of natural product antibiotics.
Topics: Anti-Bacterial Agents; Bacteria; Biological Products; Drug Resistance, Microbial; Drug Tolerance; Humans; Microbial Sensitivity Tests; Molecular Structure
PubMed: 30951303
DOI: 10.1021/acs.jmedchem.9b00370