Fentanyl and its derivatives: Pain-killers or man-killers?

Fentanyl is a synthetic µ-opioid receptor agonist approved to treat severe to moderate pain with faster onset of action and about 100 times more potent than morphine. Over last two decades, abuse of fentanyl and its derivatives has an increased trend, globally. Currently, the United States (US) faces the most serious situation related to fentanyl overdose, commonly referred to as the opioid epidemic. Nowadays, fentanyl is considered as the number one cause of death for adults aged 18-45 in the US. Synthesis and derivatization of fentanyl is inexpensive to manufacture and easily achievable. Indeed, more than 1400 fentanyl derivatives have been described in the scientific literature and patents. In addition, accessibility and efficacy of fentanyl and its derivatives can play a potential role in misuse of these compounds as a chemical weapon. In this review, the properties, general pharmacology, and overdose death cases associated with fentanyl and selected derivatives are presented. Moreover, current opioid epidemic in the US, Moscow theatre hostage crisis, and potential misuse of fentanyl and its derivatives as a chemical weapon are disclosed.

Dendrobine: A neuroprotective Sesquiterpenic Alkaloid for the Prevention and Treatment of Diseases: A Review.

A sesquiterpenic alkaloid dendrobine is the major bioactive compound extracted from Dendrobium nobile Lindl. This compound was structurally very similar to picrotoxinin (neurotoxin) containing bicyclic or tricyclic ring while dendrobine containing tetracyclic rings with up to 7 stereogenic centers showing numerous neuroprotective effects. Several sesquiterpenic alkaloids such as (+)-(1R,5R,6S,8R,9R)- 8,12-dihydroxy-copacamphan-3-en-2-one, dendrobine, denrine B, (+)- (1R,2S,3R,4S,5R,6S,9R)-3,11,12-trihydroxypicrotoxane-2(15)-lactone, dendroxine B, nobilonine, 13-Hydroxy-14-oxodendrobine, 6-Hydroxy-nobilonine and (-)-(1S,2R,3S,4R,5S,6R,9S,12R)- 3,11,13-trihydroxypicrotoxane-2(15)-lactone were isolated from D. nobile This comprehensive review summarizes the necessary information on the morphology, biochemistry and pharmacology of dendrobine. The phytochemical profile had potent in-vivo and in-vitro efficacy in neuroprotection, nerve function, memory enhancement, cognitive disorders, anxiety and depression, anti-oxidant, psychological conditions, increasing serotonin concentration in synapse anxiolytic, tranquilizing, anti-stress, neurodegenerative (Alzheimer's disease and Parkinson), anti-inflammatory and analgesic. The compound dendrobine activates neuro synapses, serotonergic synapse and signaling pathways during neurotransmission playing important role in Alzheimer's disease, Parkinson's disease, anxiety and long-term depression.

Health and Environmental Hazards of the Toxic Pteridium aquilinum (L.) Kuhn (Bracken Fern).

Bracken fern (Pteridium aquilinum (L.) Kuhn) is ubiquitous and acts as a cosmopolitan weed in pastures and similar environments. Despite its historical uses, it presents risks due to toxicity. This study, conducted in the second half of 2023, aimed to assess the environmental and health hazards of P. aquilinum, primarily focusing on its carcinogenic compound, ptaquiloside. The literature was comprehensively reviewed using diverse databases, including PubMed, Web of Science, Scopus, and Google Scholar. Information was synthesized from original research articles, meta-analyses, systematic reviews, and relevant animal studies. Animals grazing on bracken fern face annual production losses due to toxin exposure. The substantial impact on biodiversity, animal health, and human well-being arises from the presence of ptaquiloside and related compounds in milk, meat, and water, along with the increasing global prevalence of P. aquilinum and its swift colonization in acidic soil and fire-damaged areas. The objectives were to identify major bioactive compounds and explore their effects at molecular, cellular, pathological, and population levels. Various cooking techniques were considered to mitigate toxin exposure, although complete elimination remains unattainable. Therefore, the findings emphasize the need for cautious consumption. In conclusion, continued research is necessary to better understand and manage its environmental and health implications.

Contemporary mTOR inhibitor scaffolds to diseases breakdown: A patent review (2015-2021).

Mechanistic target of rapamycin (mTOR) is a highly conserved protein kinase acting as a central regulator of cell functions. The kinase forms two distinct mTOR complexes termed as mTORC1 and mTORC2. Dysregulation of mTOR activity is associated with various pathological conditions. Inhibition of overactivated mTOR represent a rational approach in the treatment of numerous human diseases. Rapamycin is a potent natural inhibitor of mTOR exhibiting significant antitumor and immunosuppressive activity. Derivatization of rapamycin provided rapalogs, the first generation of mTOR inhibitors that selectively inhibit mTORC1 activity. Further interest of research community resulted in creation of the second generation of mTOR inhibitors involving both, mTOR kinase inhibitors and dual phosphoinositide 3-kinase (PI3K)/mTOR inhibitors. Recently, combining advances of first and second generation of mTOR inhibitors yielded in the third generation of inhibitors termed as rapalinks. Nowadays, novel inhibitors belonging to all of the three generations are still under development. These inhibitors help us better to understand role of mTOR in mTOR signaling pathway as well as in diverse human diseases. In this review, we summarize recent reported mTOR inhibitors or methods of use thereof in the treatment of various diseases.

Millennium Nutrient N,N-Dimethylglycine (DMG) and its Effectiveness in Autism Spectrum Disorders.

Autism is a neurodevelopmental disorder belonging to the autism spectrum disorder (ASD). In ASDs, the individuals show substantial impairments in social communication, repetitive behaviours, and sensory behaviours deficits in the early stages of their life. Globally, the prevalence of autism is estimated to be less than 1%, especially in high- -income countries. In recent decades, there has been a drastic increase in the incidence of ASD, which has put ASD into the category of epidemics. Presently, two US Food and Drug Administration-approved drugs, aripiprazole and risperidone, are used to treat symptoms of agitation and irritability in autistic children. However, to date, no medication has been found to treat the core symptoms of ASD. The adverse side effects of conventional medicine and limited treatment options have led families of autistic children to turn to complementary and alternative medicine (CAM) treatments, which are perceived as relatively safe compared to conventional medicine. Recently N, N-dimethylglycine (DMG), a dietary supplement, has emerged as a useful supplement to improve the mental and physical state of children with ASD. The current review discusses ASD, the prevalence of ASD, the CAM approach, and the efficacy of CAM treatment in children with ASD. Moreover, it highlights the chemistry, pharmacological effect, and clinical studies of DMG, highlighting its potential for improving the lifestyle of children with ASD.

Neuropharmacology of Cevimeline and Muscarinic Drugs-Focus on Cognition and Neurodegeneration.

At present, Alzheimer's disease (AD) and related dementias cannot be cured. Therefore, scientists all over the world are trying to find a new approach to prolong an active life of patients with initial dementia. Both pharmacological and non-pharmacological pathways are investigated to improve the key symptom of the disease, memory loss. In this respect, influencing the neuromodulator acetylcholine via muscarinic receptors, such as cevimeline, might be one of the therapeutic alternatives. The purpose of this study is to explore the potential of cevimeline on the cognitive functions of AD patients. The methodology is based on a systematic literature review of available studies found in Web of Science, PubMed, Springer, and Scopus on the research topic. The findings indicate that cevimeline has shown an improvement in experimentally induced cognitive deficits in animal models. Furthermore, it has demonstrated to positively influence tau pathology and reduce the levels of amyloid-ß (Aß) peptide in the cerebral spinal fluid of Alzheimer's patients. Although this drug has not been approved by the FDA for its use among AD patients and there is a lack of clinical studies confirming and extending this finding, cevimeline might represent a breakthrough in the treatment of AD.

Rapamycin: Drug Repurposing in SARS-CoV-2 Infection.

Since December 2019, SARS-CoV-2 (COVID-19) has been a worldwide pandemic with enormous consequences for human health and the world economy. Remdesivir is the only drug in the world that has been approved for the treating of COVID-19. This drug, as well as vaccination, still has uncertain effectiveness. Drug repurposing could be a promising strategy how to find an appropriate molecule: rapamycin could be one of them. The authors performed a systematic literature review of available studies on the research describing rapamycin in association with COVID-19 infection. Only peer-reviewed English-written articles from the world's acknowledged databases Web of Science, PubMed, Springer and Scopus were involved. Five articles were eventually included in the final analysis. The findings indicate that rapamycin seems to be a suitable candidate for drug repurposing. In addition, it may represent a better candidate for COVID-19 therapy than commonly tested antivirals. It is also likely that its efficiency will not be reduced by the high rate of viral RNA mutation.

Chemistry and Toxicology of Major Bioactive Substances in Inocybe Mushrooms.

Mushroom poisoning has always been a threat to human health. There are a large number of reports about ingestion of poisonous mushrooms every year around the world. It attracts the attention of researchers, especially in the aspects of toxin composition, toxic mechanism and toxin application in poisonous mushroom. Inocybe is a large genus of mushrooms and contains toxic substances including muscarine, psilocybin, psilocin, aeruginascin, lectins and baeocystin. In order to prevent and remedy mushroom poisoning, it is significant to clarify the toxic effects and mechanisms of these bioactive substances. In this review article, we summarize the chemistry, most known toxic effects and mechanisms of major toxic substances in Inocybe mushrooms, especially muscarine, psilocybin and psilocin. Their available toxicity data (different species, different administration routes) published formerly are also summarized. In addition, the treatment and medical application of these toxic substances in Inocybe mushrooms are also discussed. We hope that this review will help understanding of the chemistry and toxicology of Inocybe mushrooms as well as the potential clinical application of its bioactive substances to benefit human beings.

Marine Invertebrate Peptides: Antimicrobial Peptides.

Antimicrobial peptides are an important component of many organisms' innate immune system, with a good inhibitory or killing effect against the invading pathogens. As a type of biological polypeptide with natural immune activities, antimicrobial peptides have a broad spectrum of antibacterial, antiviral, and antitumor activities. Nevertheless, these peptides cause no harm to the organisms themselves. Compared with traditional antibiotics, antimicrobial peptides have the advantage of not producing drug resistance and have a unique antibacterial mechanism, which has attracted widespread attention. In this study, marine invertebrates were classified into arthropods, annelids, mollusks, cnidarians, and tunicata. We then analyzed the types, sources and antimicrobial activities of the antimicrobial peptides in each group. We also reviewed the immune mechanism from three aspects: membrane-targeted direct killing effects, non-membrane targeting effects and immunomodulatory effects. Finally, we discussed their applications and the existing problems facing antimicrobial peptides in actual production. The results are expected to provide theoretical support for future research and applications of antimicrobial peptides in marine invertebrates.

Cyclosporine A: Chemistry and Toxicity - A Review.

Cyclosporine A (CsA) is a cyclic undecapeptide with strong immunosuppressive potency. Firstly marketed in the mid-1980s, CsA was widely used in transplantation and greatly improved the survival rates of patients and grafts after solid-organ transplantation. Unfortunately, CsA administration can be associated with a number of side effects due to its high toxicity. These side effects seriously limited the clinical use of CsA. Therefore, it is important to understand the serious side effects of CsA in patients, especially in transplantation. In this review article, the chemistry and most known toxic effects of CsA, including the nephrotoxic, hepatotoxic, neurotoxic, and cardiotoxic effects, are summarized. Its available toxicity data (different species, different administration routes), published formerly, are also summarized. In addition, the molecular pathways of toxicity induced by CsA are also discussed in detail. It is hoped that this review will help to further understand the source, chemistry, and clinical application of CsA in patients as well as the potential mechanisms of CsA-induced toxicity.

Flakka: New Dangerous Synthetic Cathinone on the Drug Scene.

New psychoactive substances are being used as drugs and appear to be quite popular nowadays. Thanks to their specific properties, these drugs create inimitable experiences for intoxicated people. Synthetic cathinones are the most common compounds in these new drugs. Among them, α-pyrrolidopentadione (α-PVP), or "Flakka" (street name), is one of the most famous cathinone-designed drugs. Similar to other synthetic cathinone drugs, α-PVP can effectively inhibit norepinephrine and dopamine transmitters. The adverse reactions of α-PVP mainly include mania, tachycardia, and hallucinations. An increasing number of people are being admitted to emergency wards due to the consequences of their use. This work mainly summarizes the history, synthesis, pharmacology, toxicology, structure-activity relationship, metabolism, clinical process and health risks, poisoning and death, forensic toxicology, and legal status of α-PVP. We hope this review will help bring more attention to the exploration of this substance in order to raise awareness of its negative impacts on humans.

Malus domestica: A Review on Nutritional Features, Chemical Composition, Traditional and Medicinal Value.

Fruit-derived bioactive substances have been spotlighted as a regulator against various diseases due to their fewer side effects compared to chemical drugs. Among the most frequently consumed fruits, apple is a rich source of nutritional molecules and contains high levels of bioactive compounds. The main structural classes of apple constituents include polyphenols, polysaccharides (pectin), phytosterols, and pentacyclic triterpenes. Also, vitamins and trace elements complete the nutritional features of apple fruit. There is now considerable scientific evidence that these bioactive substances present in apple and peel have the potential to improve human health, for example contributing to preventing cardiovascular disease, diabetes, inflammation, and cancer. This review will focus on the current knowledge of bioactive substances in apple and their medicinal value for human health.

Phenytoin - An anti-seizure drug: Overview of its chemistry, pharmacology and toxicology.

Phenytoin is a long-standing, anti-seizure drug widely used in clinical practice. It has also been evaluated in the context of many other illnesses in addition to its original epilepsy indication. The narrow therapeutic index of phenytoin and its ubiquitous daily use pose a high risk of poisoning. This review article focuses on the chemistry, pharmacokinetics, and toxicology of phenytoin, with a special focus on its mutagenicity, carcinogenicity, and teratogenicity. The side effects on human health associated with phenytoin use are thoroughly described. In particular, DRESS syndrome and cerebellar atrophy are addressed. This review will help in further understanding the benefits phenytoin use in the treatment of epilepsy.

Digoxin: Pharmacology and toxicology-A review.

Digoxin is a cardiac glycoside used as drug in case of heart problems, including congestive heart failure, atrial fibrillation or flutter, and certain cardiac arrhythmias. It has a very narrow therapeutic window of the medication. Digoxin is toxic substance with well known cardiotoxic effect. In this work, pharmacology and toxicology of digoxin are summarized; Its pharmacokinetics, pharmacodynamics, available acute toxicity data (different species, different administration routes) are summarized in this article. Moreover, its treatment side effect and human poisonings are thoroughly discussed. Finally, appropriate therapy regimen is proposed.

Jatropha gossypiifolia L. and its biologically active metabolites: A mini review.

ETHNOPHARMACOLOGICAL RELEVANCE: Jatropha gossypiifolia L. (Euphorbiaceae) is popularly known as bellyache bush or black physic nut and is widely used in local / traditional medicine due to the various biological activities attributed to its different parts, including its leaves, roots, and latex. AIM OF THE STUDY: In this review, we aim to update and discuss the chemistry, specific pharmacology, and toxicological activities of Jatropha gossypiifolia and its bioactive metabolites. MATERIALS AND METHODS: The Web of Science, PubMed, Google Scholar, SciFinder, Cochrane Library, Scopus, and Science Direct databases were searched with the name "Jatropha gossypiifolia" and the term "bioactive metabolites". All studies on the chemistry, pharmacology, and toxicology of the plant up to December 2018 were included in this review. RESULTS: Jatropha gossypiifolia leaves are considered to have anti-inflammatory, antimicrobial and insecticidal properties. The root and stem have anti-inflammatory and antimicrobial properties. The seeds and fruits can be used against influenza and as a sedative, analgesic or anti-diarrheal agents. The latex is bactericidal and molluscicidal. Topical application of latex is used to treat wounds and bites of venomous animals. The diluted form is usually used for the treatment of diarrhoea by indigenous peoples. CONCLUSIONS: The main pharmacological activities of Jatropha gossypiifolia include anti-inflammatory, antineoplastic, antimicrobial, antioxidant, and anticholinesterase, and antihypertensive activities. Species of Jatropha are notably known for their toxic potential, and their toxicity is primarily related to the latex and seed contents. However, the potential mechanisms of these pharmacological activities have not been fully explored. We hope this review will help to further inform the potential utilization of Jatropha gossypiifolia in complementary and alternative medicine.

Antimicrobial Peptides: Amphibian Host Defense Peptides.

Antimicrobial Peptides (AMPs) are one of the most common components of the innate immune system that protect multicellular organisms against microbial invasion. The vast majority of AMPs are isolated from the frog skin. Anuran (frogs and toads) skin contains abundant AMPs that can be developed therapeutically. Such peptides are a unique but diverse group of molecules. In general, more than 50% of the amino acid residues form the hydrophobic part of the molecule. Normally, there are no conserved structural motifs responsible for activity, although the vast majority of the AMPs are cationic due to the presence of multiple lysine residues; this cationicity has a close relationship with antibacterial activity. Notably, recent evidence suggests that synthesis of AMPs in frog skin may confer an advantage on a particular species, although they are not essential for survival. Frog skin AMPs exert potent activity against antibiotic-resistant bacteria, protozoa, yeasts, and fungi by permeating and destroying the plasma membrane and inactivating intracellular targets. Importantly, since they do not bind to a specific receptor, AMPs are less likely to induce resistance mechanisms. Currently, the best known amphibian AMPs are esculentins, brevinins, ranacyclins, ranatuerins, nigrocin-2, magainins, dermaseptins, bombinins, temporins, and japonicins-1 and -2, and palustrin-2. This review focuses on these frog skin AMPs and the mechanisms underlying their antimicrobial activity. We hope that this review will provide further information that will facilitate further study of AMPs and cast new light on novel and safer microbicides.

Beauvericin, A Fusarium Mycotoxin: Anticancer Activity, Mechanisms, and Human Exposure Risk Assessment.

Beauvericin (BEA) is a cyclic hexadepsipeptide, which derives from Cordyceps cicadae. It is also produced by Fusarium species, which are parasitic to maize, wheat, rice and other important commodities. BEA increases ion permeability in biological membranes by forming a complex with essential cations, which may affect ionic homeostasis. Its ion-complexing capability allows BEA to transport alkaline earth metal and alkali metal ions across cell membranes. Importantly, increasing lines of evidence show that BEA has an anticancer effect and can be potentially used in cancer therapeutics. Normally, BEA performs the anticancer effect due to the induced cancer cell apoptosis via a reactive oxygen species-dependent pathway. Moreover, BEA increases the intracellular Ca2+ levels and subsequently regulates the activity of a series of signalling pathways including MAPK, JAK/STAT, and NF-κB, and finally causes cancer cell apoptosis. In vivo studies further show that BEA reduces tumour volumes and weights. BEA especially targets differentiated and invasive cancer types. Currently, the anticancer activity of BEA is a hot topic; however, there is no review article to discuss the anticancer activity of BEA. Therefore, in this review, we have mainly summarized the anticancer activity of BEA and thoroughly discussed its underlying mechanisms. In addition, the human exposure risk assessment of BEA is also discussed. We hope that this review will provide further information for understanding the anticancer mechanisms of BEA.

A Review on the Synthesis and Bioactivity Aspects of Beauvericin, a Fusarium Mycotoxin.

Beauvericin (BEA) is an emerging Fusarium mycotoxin that contaminates food and feeds globally. BEA biosynthesis is rapidly catalyzed by BEA synthetase through a nonribosomal, thiol-templated mechanism. This mycotoxin has cytotoxicity and is capable of increasing oxidative stress to induce cell apoptosis. Recently, large evidence further shows that this mycotoxin has a variety of biological activities and is being considered a potential candidate for medicinal and pesticide research. It is noteworthy that BEA is a potential anticancer agent since it can increase the intracellular Ca2+ levels and induce the cancer cell death through oxidative stress and apoptosis. BEA has exhibited effective antibacterial activities against both pathogenic Gram-positive and Gram-negative bacteria. Importantly, BEA exhibits an effective capacity to inhibit the human immunodeficiency virus type-1 integrase. Moreover, BEA can simultaneously target drug resistance and morphogenesis which provides a promising strategy to combat life-threatening fungal infections. Thus, in this review, the synthesis and the biological activities of BEA, as well as, the underlying mechanisms, are fully analyzed. The risk assessment of BEA in food and feed are also discussed. We hope this review will help to further understand the biological activities of BEA and cast some new light on drug discovery.

Insect Antimicrobial Peptides, a Mini Review.

Antimicrobial peptides (AMPs) are crucial effectors of the innate immune system. They provide the first line of defense against a variety of pathogens. AMPs display synergistic effects with conventional antibiotics, and thus present the potential for combined therapies. Insects are extremely resistant to bacterial infections. Insect AMPs are cationic and comprise less than 100 amino acids. These insect peptides exhibit an antimicrobial effect by disrupting the microbial membrane and do not easily allow microbes to develop drug resistance. Currently, membrane mechanisms underlying the antimicrobial effects of AMPs are proposed by different modes: the barrel-stave mode, toroidal-pore, carpet, and disordered toroidal-pore are the typical modes. Positive charge quantity, hydrophobic property and the secondary structure of the peptide are important for the antibacterial activity of AMPs. At present, several structural families of AMPs from insects are known (defensins, cecropins, drosocins, attacins, diptericins, ponericins, metchnikowins, and melittin), but new AMPs are frequently discovered. We reviewed the biological effects of the major insect AMPs. This review will provide further information that facilitates the study of insect AMPs and shed some light on novel microbicides.

Tetramethylenedisulfotetramine: A Health Risk Compound and a Potential Chemical Warfare Agent.

Tetramethylenedisulfotetramine (TETS, tetramine) is a toxic organic compound that is used as an effective rodenticide. However, this neurotoxin is not only toxic to rodents, it also causes poisoning in humans. Due to its high level of toxicity for humans, the use of TETS as a rodenticide has been banned and its production has been discontinued. Despite this, human poisoning by this substance is unfortunately still very common. The largest number of poisonings are reported in China, but in the United States, dozens of poisonings still happen annually. TETS is one of the most hazardous pesticides and also a possible chemical warfare agent with no known antidote. In this article, we aim to summarize the biochemical and toxicological data of TETS and hope to cast some light on the toxicological risk to human health.