Showing papers in "Frontiers in Pharmacology in 2021"
TL;DR: In this paper, the authors reviewed the mechanistic action of heavy metals according to the available animal and human studies and found similar pathways for these metals to induce toxicity including ROS generation, weakening of the antioxidant defense, enzyme inactivation, and oxidative stress.
Abstract: The industrial activities of the last century have caused massive increases in human exposure to heavy metals. Mercury, lead, chromium, cadmium, and arsenic have been the most common heavy metals that induced human poisonings. Here, we reviewed the mechanistic action of these heavy metals according to the available animal and human studies. Acute or chronic poisonings may occur following exposure through water, air, and food. Bioaccumulation of these heavy metals leads to a diversity of toxic effects on a variety of body tissues and organs. Heavy metals disrupt cellular events including growth, proliferation, differentiation, damage-repairing processes, and apoptosis. Comparison of the mechanisms of action reveals similar pathways for these metals to induce toxicity including ROS generation, weakening of the antioxidant defense, enzyme inactivation, and oxidative stress. On the other hand, some of them have selective binding to specific macromolecules. The interaction of lead with aminolevulinic acid dehydratase and ferrochelatase is within this context. Reactions of other heavy metals with certain proteins were discussed as well. Some toxic metals including chromium, cadmium, and arsenic cause genomic instability. Defects in DNA repair following the induction of oxidative stress and DNA damage by the three metals have been considered as the cause of their carcinogenicity. Even with the current knowledge of hazards of heavy metals, the incidence of poisoning remains considerable and requires preventive and effective treatment. The application of chelation therapy for the management of metal poisoning could be another aspect of heavy metals to be reviewed in the future.
479 citations
TL;DR: In this paper, the use of polymeric nanoparticles as drug delivery systems of anticancer compounds, their physico-chemical properties and their ability to be efficiently localized in specific tumor tissues have been described.
Abstract: Advances in nanotechnology have favored the development of novel colloidal formulations able to modulate the pharmacological and biopharmaceutical properties of drugs. The peculiar physico-chemical and technological properties of nanomaterial-based therapeutics have allowed for several successful applications in the treatment of cancer. The size, shape, charge and patterning of nanoscale therapeutic molecules are parameters that need to be investigated and modulated in order to promote and optimize cell and tissue interaction. In this review, the use of polymeric nanoparticles as drug delivery systems of anticancer compounds, their physico-chemical properties and their ability to be efficiently localized in specific tumor tissues have been described. The nanoencapsulation of antitumor active compounds in polymeric systems is a promising approach to improve the efficacy of various tumor treatments.
169 citations
TL;DR: In this article, a review of the physiological, and pharmaceutical barriers influencing drug bioavailability for the oral route of administration, as well as the conventional and novel drug delivery strategies are discussed.
Abstract: The oral route is the most common route for drug administration. It is the most preferred route, due to its advantages, such as non-invasiveness, patient compliance and convenience of drug administration. Various factors govern oral drug absorption including drug solubility, mucosal permeability, and stability in the gastrointestinal tract environment. Attempts to overcome these factors have focused on understanding the physicochemical, biochemical, metabolic and biological barriers which limit the overall drug bioavailability. Different pharmaceutical technologies and drug delivery systems including nanocarriers, micelles, cyclodextrins and lipid-based carriers have been explored to enhance oral drug absorption. To this end, this review will discuss the physiological, and pharmaceutical barriers influencing drug bioavailability for the oral route of administration, as well as the conventional and novel drug delivery strategies. The challenges and development aspects of pediatric formulations will also be addressed.
164 citations
TL;DR: In this paper, a comparative bioprospecting for a group of wild orchids using EBDCS (the Economic Botany Data Collection Standards) organ targeted and biological response methods was carried out.
Abstract: Necklace orchids (Coelogyninae, Epidendroideae) have been used in traditional medicine practices for centuries. Previous studies on a subset of unrelated orchid species utilized in these traditional practices revealed they possessed antimicrobial, anti-inflammatory, and anti-oxidant activity, providing experimental proof for their medicinal properties. To date however none of these species have been investigated ethno-botanically in a phylogenetic context. This study carried out comparative bioprospecting for a group of wild orchids using EBDCS (the Economic Botany Data Collection Standards) organ targeted and biological response methods. The traditional medicinal use of necklace orchids was recorded from books and journals published between 1984 and 2016. Two orchids, Coelogyne cristata and Coelogyne fimbriata, were selected, cultivated both indoors and outdoors, and the antimicrobial properties on extracts from their leaves and pseudobulbs tested against a selection of human pathogens. A molecular phylogeny of Coelogyninae based on nuclear ribosomal ITS and plastid matK DNA sequences obtained from 148 species was reconstructed with Maximum Likelihood (ML) using RAxML, Maximum Parsimony (MP) using PAUP and Bayesian Inference using MrBayes. Bioprospecting comparison of EBDCS and biological response was carried out using customized R scripts. Ethanolic extracts obtained from leaves of C. fimbriata inhibited growth of Bacillus cereus, Staphylococcus aureus, and Yersinia enterocolitica, confirming the antimicrobial properties of these extracts. Leaf extracts were found to have slightly stronger antimicrobial properties for plants cultivated outdoors than indoors. These differences were not found to be statistically significant though. Three hot nodes with high potency for antimicrobial activities were detected with the EBDCS organ targeted classification method, and eight hot nodes were detected with the biological response classification method. The biological response classification method is thus a more effective tool in finding hot nodes amongst clades of species with high medicinal potential.
142 citations
TL;DR: A better understanding of the biology and the regulatory mechanisms of DNA repair pathway has the potential to facilitate the development of inhibitors of nuclear and mitochondria DNA repair pathways for enhancing anticancer effect of DNA damage-based therapy as mentioned in this paper.
Abstract: DNA repair pathways are triggered to maintain genetic stability and integrity when mammalian cells are exposed to endogenous or exogenous DNA-damaging agents. The deregulation of DNA repair pathways is associated with the initiation and progression of cancer. As the primary anti-cancer therapies, ionizing radiation and chemotherapeutic agents induce cell death by directly or indirectly causing DNA damage, dysregulation of the DNA damage response may contribute to hypersensitivity or resistance of cancer cells to genotoxic agents and targeting DNA repair pathway can increase the tumor sensitivity to cancer therapies. Therefore, targeting DNA repair pathways may be a potential therapeutic approach for cancer treatment. A better understanding of the biology and the regulatory mechanisms of DNA repair pathways has the potential to facilitate the development of inhibitors of nuclear and mitochondria DNA repair pathways for enhancing anticancer effect of DNA damage-based therapy.
114 citations
TL;DR: In this paper, the role of oxLDL in atherosclerosis development on different levels is discussed, and it suggests that LDL particles undergo numerous modifications that change their size, density and chemical properties within the blood flow and vascular wall.
Abstract: Cardiovascular pathologies maintain the leading position in mortality worldwide. Atherosclerosis is a chronic disease that can result in a variety of serious complications, such as myocardial infarction, stroke, and cardiovascular disease. Inflammation and lipid metabolism alterations play a crucial role in atherogenesis, but the details of relationships and causality of these fundamental processes remain not clear. The oxidation of LDL was considered the main atherogenic modification of LDL within the vascular wall for decades. However, recent investigations provided a growing body of evidence in support of the multiple LDL modification theory. It suggests that LDL particles undergo numerous modifications that change their size, density, and chemical properties within the blood flow and vascular wall. Oxidation is the last stage in this cascade resulting in the atherogenic properties. Moreover, recent investigations have discovered that oxLDL may have both anti-inflammatory and pro-inflammatory properties. Oxidized LDL can trigger inflammation through the activation of macrophages and other cells. After all, oxidized LDL is still a promising object for further investigations that have the potential to clarify the unknown parts of the atherogenic process. In this review, we discuss the role of oxLDL in atherosclerosis development on different levels.
111 citations
TL;DR: Fluvoxamine is a well-tolerated, widely available, inexpensive selective serotonin reuptake inhibitor that has been shown in a small, double-blind, placebo-controlled, randomized study to prevent clinical deterioration of patients with mild coronavirus disease 2019 (COVID-19) as mentioned in this paper.
Abstract: Fluvoxamine is a well-tolerated, widely available, inexpensive selective serotonin reuptake inhibitor that has been shown in a small, double-blind, placebo-controlled, randomized study to prevent clinical deterioration of patients with mild coronavirus disease 2019 (COVID-19). Fluvoxamine is also an agonist for the sigma-1 receptor, through which it controls inflammation. We review here a body of literature that shows important mechanisms of action of fluvoxamine and other SSRIs that could play a role in COVID-19 treatment. These effects include: reduction in platelet aggregation, decreased mast cell degranulation, interference with endolysosomal viral trafficking, regulation of inositol-requiring enzyme 1α-driven inflammation and increased melatonin levels, which collectively have a direct antiviral effect, regulate coagulopathy or mitigate cytokine storm, which are known hallmarks of severe COVID-19.
106 citations
TL;DR: In this article, the authors summarize the critical role of the PI3K/AKT/mTOR pathway in drug resistance, the development of PI3k/AKt/mtor inhibitors, and strategies to overcome acquired resistance to standard therapies in breast cancer.
Abstract: Although chemotherapy, targeted therapy and endocrine therapy decrease rate of disease recurrence in most breast cancer patients, many patients exhibit acquired resistance. Hyperactivation of the PI3K/AKT/mTOR pathway is associated with drug resistance and cancer progression. Currently, a number of drugs targeting PI3K/AKT/mTOR are being investigated in clinical trials by combining them with standard therapies to overcome acquired resistance in breast cancer. In this review, we summarize the critical role of the PI3K/AKT/mTOR pathway in drug resistance, the development of PI3K/AKT/mTOR inhibitors, and strategies to overcome acquired resistance to standard therapies in breast cancer.
104 citations
TL;DR: In this article, the structure and mechanisms of PROTACs and several classes of effective PROTAC degraders based on E3 ligases are described, and the first oral PROTAC (ARV-110 and ARV-471) have shown encouraging results in clinical trials for prostate and breast cancer treatment.
Abstract: Proteolysis targeting chimeric (PROTAC) technology is an effective endogenous protein degradation tool developed in recent years that can ubiquitinate the target proteins through the ubiquitin-proteasome system (UPS) to achieve an effect on tumor growth. A number of literature studies on PROTAC technology have proved an insight into the feasibility of PROTAC technology to degrade target proteins. Additionally, the first oral PROTACs (ARV-110 and ARV-471) have shown encouraging results in clinical trials for prostate and breast cancer treatment, which inspires a greater enthusiasm for PROTAC research. Here we focus on the structures and mechanisms of PROTACs and describe several classes of effective PROTAC degraders based on E3 ligases.
101 citations
Shahid Beheshti University of Medical Sciences and Health Services1, Arturo Prat University2, Mohammed V University3, Government College University, Faisalabad4, Dow University of Health Sciences5, University of Medicine and Pharmacy of Craiova6, Carol Davila University of Medicine and Pharmacy7, National Autonomous University of Mexico8, Presidency University, Kolkata9, University of Concepción10, University of Zaragoza11
TL;DR: In this article, a review comprehensively describes preclinical studies on chalcones and their derivatives describing their immense significance as antidiabetic, anticancer, anti-inflammatory, antimicrobial, antioxidant, antiparasitic, psychoactive, and neuroprotective agents.
Abstract: Chalcones are among the leading bioactive flavonoids with a therapeutic potential implicated to an array of bioactivities investigated by a series of preclinical and clinical studies. In this article, different scientific databases were searched to retrieve studies depicting the biological activities of chalcones and their derivatives. This review comprehensively describes preclinical studies on chalcones and their derivatives describing their immense significance as antidiabetic, anticancer, anti-inflammatory, antimicrobial, antioxidant, antiparasitic, psychoactive, and neuroprotective agents. Besides, clinical trials revealed their use in the treatment of chronic venous insufficiency, skin conditions, and cancer. Bioavailability studies on chalcones and derivatives indicate possible hindrance and improvement in relation to its nutraceutical and pharmaceutical applications. Multifaceted and complex underlying mechanisms of chalcone actions demonstrated their ability to modulate a number of cancer cell lines, to inhibit a number of pathological microorganisms and parasites, and to control a number of signaling molecules and cascades related to disease modification. Clinical studies on chalcones revealed general absence of adverse effects besides reducing the clinical signs and symptoms with decent bioavailability. Further studies are needed to elucidate their structure activity, toxicity concerns, cellular basis of mode of action, and interactions with other molecules.
97 citations
TL;DR: Wang et al. as mentioned in this paper reviewed the relationship between AKT signaling pathway and AD and PD, and discussed the potential natural products based on the PI3K/AKT pathway to treat two diseases in recent years.
Abstract: Alzheimer's disease (AD) and Parkinson's disease (PD) are two typical neurodegenerative diseases that increased with aging. With the emergence of aging population, the health problem and economic burden caused by the two diseases also increase. Phosphatidylinositol 3-kinases/protein kinase B (PI3K/AKT) signaling pathway regulates signal transduction and biological processes such as cell proliferation, apoptosis and metabolism. According to reports, it regulates neurotoxicity and mediates the survival of neurons through different substrates such as forkhead box protein Os (FoxOs), glycogen synthase kinase-3β (GSK-3β), and caspase-9. Accumulating evidences indicate that some natural products can play a neuroprotective role by activating PI3K/AKT pathway, providing an effective resource for the discovery of potential therapeutic drugs. This article reviews the relationship between AKT signaling pathway and AD and PD, and discusses the potential natural products based on the PI3K/AKT signaling pathway to treat two diseases in recent years, hoping to provide guidance and reference for this field. Further development of Chinese herbal medicine is needed to treat these two diseases.
TL;DR: The role of mesenchymal stem cells (MSC-exosomes) as a nanocarrier, drug loading and tissue engineering has been discussed in this article, and their potential contribution in a series of diseases as well as the advantages of exosomes over stem cells and synthetic nanoparticles and potential disadvantages.
Abstract: As nano-scale biological vesicles, extracellular vesicles (EVs)/exosomes, in particular, exosomes derived from mesenchymal stem cells (MSC-exosomes), have been studied in the diagnosis, prevention, and treatment of many diseases. In addition, through the combination of nanotechnology and biotechnology, exosomes have emerged as innovative tools for the development of nanomedicine. This review focuses on a profound summarization of MSC-exosomes as a powerful tool in bionanomedicine. It systemically summarizes the role of MSC-exosomes as a nanocarrier, drug loading and tissue engineering, and their potential contribution in a series of diseases as well as the advantages of exosomes over stem cells and synthetic nanoparticles and potential disadvantages. The in-depth understanding of the functions and mechanisms of exosomes provides insights into the basic research and clinical transformation in the field of nanomedicine.
Shahid Beheshti University of Medical Sciences and Health Services1, Arturo Prat University2, University of Porto3, Central University, India4, Shobhit University5, The Volgograd State Medical University6, North-Caucasus Federal University7, Memorial University of Newfoundland8, Tajik Academy of Sciences9, University of Naples Federico II10, Medical University of Lublin11
TL;DR: In this paper, a review of the potential of phytosterols in terms of their therapeutic potential for human health, also emphasizing their pre-clinical effects and bioavailability related issues.
Abstract: Phytosterols (PSs) are plant-originated steroids. Over 250 PSs have been isolated, and each plant species contains a characteristic phytosterol composition. A wide number of studies have reported remarkable pharmacological effects of PSs, acting as chemo-preventive, anti-inflammatory, antioxidant, antidiabetic, and anti-atherosclerotic agents. However, PS bioavailability is a key issue, as it can be influenced by several factors (type, source, processing, preparation, delivery method, food matrix, dose, time of administration into the body, and genetic factors), and the existence of a close relationship between their chemical structures (e.g., saturation degree and side chain length) and low absorption rates has been stated. In this sense, the present review intends to provide in-depth data on PS therapeutic potential for human health, also emphasizing their pre-clinical effects and bioavailability-related issues.
TL;DR: Kaempferol (KPF) is a flavonoid antioxidant found in fruits and vegetables, which has shown a multipotential neuroprotective action through the modulation of several proinflammatory signaling pathways such as the nuclear factor kappa B (NF-kB), p38 mitogen-activated protein kinases (p38MAPK), serine/threonine kinase (AKT), and β-catenin cascade.
Abstract: Kaempferol (KPF) is a flavonoid antioxidant found in fruits and vegetables. Many studies have described the beneficial effects of dietary KPF in reducing the risk of chronic diseases, especially cancer. Nevertheless, little is known about the cellular and molecular mechanisms underlying KPF actions in the central nervous system (CNS). Also, the relationship between KPF structural properties and their glycosylation and the biological benefits of these compounds is unclear. The aim of this study was to review studies published in the PubMed database during the last 10 years (2010-2020), considering only experimental articles that addressed the isolated cell effect of KPF (C15H10O6) and its derivatives in neurological diseases such as Alzheimer's disease, Parkinson, ischemia stroke, epilepsy, major depressive disorder, anxiety disorders, neuropathic pain, and glioblastoma. 27 publications were included in the present review, which presented recent advances in the effects of KPF on the nervous system. KPF has presented a multipotential neuroprotective action through the modulation of several proinflammatory signaling pathways such as the nuclear factor kappa B (NF-kB), p38 mitogen-activated protein kinases (p38MAPK), serine/threonine kinase (AKT), and β-catenin cascade. In addition, there are different biological benefits and pharmacokinetic behaviors between KPF aglycone and its glycosides. The antioxidant nature of KPF was observed in all neurological diseases through MMP2, MMP3, and MMP9 metalloproteinase inhibition; reactive oxygen species generation inhibition; endogenous antioxidants modulation as superoxide dismutase and glutathione; formation and aggregation of beta-amyloid (β-A) protein inhibition; and brain protective action through the modulation of brain-derived neurotrophic factor (BDNF), important for neural plasticity. In conclusion, we suggest that KPF and some glycosylated derivatives (KPF-3-O-rhamnoside, KPF-3-O-glucoside, KPF-7-O-rutinoside, and KPF-4'-methyl ether) have a multipotential neuroprotective action in CNS diseases, and further studies may make the KPF effect mechanisms in those pathologies clearer. Future in vivo studies are needed to clarify the mechanism of KPF action in CNS diseases as well as the impact of glycosylation on KPF bioactivity.
TL;DR: In this article, the authors reviewed the AYUSH recommended formulations and their ingredients, routinely used medicinal plants and formulations by Indian population as well as other promising Indian medicinal plants, which can be tested against COVID-19.
Abstract: The cases of COVID-19 are still increasing day-by-day worldwide, even after a year of its first occurrence in Wuhan city of China. The spreading of SARS-CoV-2 infection is very fast and different from other SARS-CoV infections possibly due to structural differences in S proteins. The patients with severe diseases may die due to acute respiratory distress syndrome (ARDS) caused by systemic inflammatory reactions due to the excessive release of pro-inflammatory cytokines and chemokines by the immune effector cells. In India too, it is spreading very rapidly, although the case fatality rate is below 1.50% (https://www.statista.com), which is markedly less than in other countries, despite the dense population and minimal health infrastructure in rural areas. This may be due to the routine use of many immunomodulator medicinal plants and traditional AYUSH formulations by the Indian people. This communication reviews the AYUSH recommended formulations and their ingredients, routinely used medicinal plants and formulations by Indian population as well as other promising Indian medicinal plants, which can be tested against COVID-19. Special emphasis is placed on Indian medicinal plants reported for antiviral, immunomodulatory and anti-allergic/anti-inflammatory activities and they are categorized for prioritization in research on the basis of earlier reports. The traditional AYUSH medicines currently under clinical trials against COVID-19 are also discussed as well as furtherance of pre-clinical and clinical testing of the potential traditional medicines against COVID-19 and SARS-CoV-2. The results of the clinical studies on AYUSH drugs will guide the policymakers from the AYUSH systems of medicines to maneuver their policies for public health, provide information to the global scientific community and could form a platform for collaborative studies at national and global levels. It is thereby suggested that promising AYUSH formulations and Indian medicinal plants must be investigated on a priority basis to solve the current crisis.
TL;DR: In this paper, the effects of curcumin administered with bioperine (to optimize absorption) in patients with Coronavirus disease-2019 (COVID-19) in a double-blind, randomized, controlled trial at a 30-bed dedicated COVID Health Center (DCHC) in Maharashtra, India.
Abstract: Background: Coronavirus disease-2019 (COVID-19) has a wide range of pathophysiological effects. Curcumin, an active constituent of Curcuma longa (turmeric), has several properties, including anti-inflammatory, antioxidant, antiviral, anti-thrombotic, and anti-proliferative effects, which make it a promising candidate for the treatment of COVID-19. Objective: We aimed to determine the effects of curcumin administered with bioperine (to optimize absorption) in patients with COVID-19 in a double-blind, randomized, controlled trial at a 30-bed dedicated COVID Health Center (DCHC) in Maharashtra, India. Methods: In addition to conventional COVID-19 treatment, patients in the control group received a dose of probiotic twice a day, and patients in the study group received curcumin (525 mg) with bioperine (2.5 mg) in tablet form twice a day. The effects of curcumin/bioperine treatment on primary and secondary outcomes were assessed for the duration of hospitalization. Results: Patients with mild, moderate, and severe symptoms who received curcumin/bioperine treatment showed early symptomatic recovery, less deterioration, fewer red flag signs, better ability to maintain oxygen saturation above 94% on room air, and better clinical outcomes compared to patients of the control group. Further, curcumin/bioperine treatment appeared to reduce duration of hospitalization in patients with moderate to severe symptoms, and fewer deaths were observed in the curcumin/bioperine treatment group. Conclusion: Administration of oral curcumin with bioperine as an adjuvant therapy in COVID-19 treatment could substantially reduce morbidity and mortality, and ease the logistical and supply-related burdens on the healthcare system. Curcumin can be a safe and natural therapeutic option to prevent Post-Covid thromboembolic events. Trial Registration: This trial is registered at clinicaltrials.gov (http://www.clinicaltrials.gov) with the identifier CTRI/2020/05/025482.
TL;DR: It is shown that oxidative stress plays a role in the etiology of ovarian aging and promotes the development of other ovarian aging-related etiologies, including telomere shortening, mitochondrial dysfunction, apoptosis, and inflammation, which raises the prospect of oxidative stress modulator-natural antioxidants as therapeutic interventions for delaying ovarian aging.
Abstract: The ovarian system comprises vital organs in females and is of great significance for the maintenance of reproductive potential and endocrine stability. Although complex pathogenesis undoubtedly contributes to ovarian aging, increasing attention is being paid to the extensive influence of oxidative stress. However, the role of oxidative stress in ovarian aging is yet to be fully elucidated. Exploring oxidative stress-related processes might be a promising strategy against ovarian aging. In this review, compelling evidence is shown that oxidative stress plays a role in the etiology of ovarian aging and promotes the development of other ovarian aging-related etiologies, including telomere shortening, mitochondrial dysfunction, apoptosis, and inflammation. In addition, some natural antioxidants such as quercetin, resveratrol, and curcumin have a protective role in the ovaries through multiple mechanisms. These findings raise the prospect of oxidative stress modulator-natural antioxidants as therapeutic interventions for delaying ovarian aging.
TL;DR: A review of the available evidence on AKT inhibition in breast cancer, reporting both efficacy and toxicity data from clinical trials along with the available translational correlates and then focusing on the potential use of these drugs in new combination strategies is presented in this paper.
Abstract: The serine/threonine kinase AKT is a key component of the PI3K/AKT/mTOR signaling pathway as it exerts a pivotal role in cell growth, proliferation, survival, and metabolism. Deregulation of this pathway is a common event in breast cancer including hormone receptor-positive (HR+) disease, HER2-amplified, and triple negative tumors. Hence, targeting AKT represents an attractive treatment option for many breast cancer subtypes, especially those resistant to conventional treatments. Several AKT inhibitors have been recently developed and two ATP-competitive compounds, capivasertib and ipatasertib, have been extensively tested in phase I and II clinical trials either alone, with chemotherapy, or with hormonal agents. Additionally, phase III trials of capivasertib and ipatasertib are already under way in HR+ and triple-negative breast cancer. While the identification of predictive biomarkers of response and resistance to AKT inhibition represents an unmet need, new combination strategies are under investigation aiming to boost the therapeutic efficacy of these drugs. As such, trials combining capivasertib and ipatasertib with CDK4/6 inhibitors, immune checkpoint inhibitors, and PARP inhibitors are currently ongoing. This review summarizes the available evidence on AKT inhibition in breast cancer, reporting both efficacy and toxicity data from clinical trials along with the available translational correlates and then focusing on the potential use of these drugs in new combination strategies.
TL;DR: Many evidence based pharmacogenetics guidelines with clear recommendations are available for clinical decision making by healthcare professionals, patients and other stakeholders.
Abstract: Many studies have shown that the efficacy and risk of side effects of drug treatment is influenced by genetic variants. Evidence based guidelines are essential for implementing pharmacogenetic knowledge in daily clinical practice to optimize pharmacotherapy of individual patients. A literature search was performed to select committees developing guidelines with recommendations being published in English. The Dutch Pharmacogenetics Working Group (DPWG), the Clinical Pharmacogenetics Implementation Consortium (CPIC), the Canadian Pharmacogenomics Network for Drug Safety (CPNDS), and the French National Network (Reseau) of Pharmacogenetics (RNPGx) were selected. Their guidelines were compared with regard to the methodology of development, translation of genotypes to predicted phenotypes, pharmacotherapeutic recommendations and recommendations on genotyping. A detailed overview of all recommendations for gene-drug combinations is given. The committees have similar methodologies of guideline development. However, the objectives differed at the start of their projects, which have led to unique profiles and strengths of their guidelines. DPWG and CPIC have a main focus on pharmacotherapeutic recommendations for a large number of drugs in combination with a patient's genotype or predicted phenotype. DPWG, CPNDS and RNPGx also recommend on performing genetic testing in daily clinical practice, with RNPGx even describing specific clinical settings or medical conditions for which genotyping is recommended. Discordances exist, however committees also initiated harmonizing projects. The outcome of a consensus project was to rename "extensive metabolizer (EM)" to "normal metabolizer (NM)". It was decided to translate a CYP2D6 genotype with one nonfunctional allele (activity score 1.0) into the predicted phenotype of intermediate metabolizer (IM). Differences in recommendations are the result of the methodologies used, such as assessment of dose adjustments of tricyclic antidepressants. In some cases, indication or dose specific recommendations are given for example for clopidogrel, codeine, irinotecan. The following drugs have recommendations on genetic testing with the highest level: abacavir (HLA), clopidogrel (CYP2C19), fluoropyrimidines (DPYD), thiopurines (TPMT), irinotecan (UGT1A1), codeine (CYP2D6), and cisplatin (TPMT). The guidelines cover many drugs and genes, genotypes, or predicted phenotypes. Because of this and their unique features, considering the totality of guidelines are of added value. In conclusion, many evidence based pharmacogenetics guidelines with clear recommendations are available for clinical decision making by healthcare professionals, patients and other stakeholders.
TL;DR: It is proposed that the principal famotidine mechanism of action for COVID-19 involves on-target histamine receptor H2 activity, and that development of clinical COVID -19 involves dysfunctional mast cell activation and histamine release.
Abstract: SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. SARS-CoV-2 infection is necessary but not sufficient for development of clinical COVID-19 disease. Currently, there are no approved pre- or post-exposure prophylactic COVID-19 medical countermeasures. Clinical data suggest that famotidine may mitigate COVID-19 disease, but both mechanism of action and rationale for dose selection remain obscure. We have investigated several plausible hypotheses for famotidine activity including antiviral and host-mediated mechanisms of action. We propose that the principal mechanism of action of famotidine for relieving COVID-19 symptoms involves on-target histamine receptor H2 activity, and that development of clinical COVID-19 involves dysfunctional mast cell activation and histamine release. Based on these findings and associated hypothesis, new COVID-19 multi-drug treatment strategies based on repurposing well-characterized drugs are being developed and clinically tested, and many of these drugs are available worldwide in inexpensive generic oral forms suitable for both outpatient and inpatient treatment of COVID-19 disease.
TL;DR: In this paper, the authors summarized recent aspects in the understanding of relevant pathways, cellular and molecular drivers of hepatic fibrosis and discuss how this knowledge can impact the therapy of respective disease.
Abstract: The liver is a central organ in the human body, coordinating several key metabolic roles. The structure of the liver which consists of the distinctive arrangement of hepatocytes, hepatic sinusoids, the hepatic artery, portal vein and the central vein, is critical for its function. Due to its unique position in the human body, the liver interacts with components of circulation targeted for the rest of the body and in the process, it is exposed to a vast array of external agents such as dietary metabolites and compounds absorbed through the intestine, including alcohol and drugs, as well as pathogens. Some of these agents may result in injury to the cellular components of liver leading to the activation of the natural wound healing response of the body or fibrogenesis. Long-term injury to liver cells and consistent activation of the fibrogenic response can lead to liver fibrosis such as that seen in chronic alcoholics or clinically obese individuals. Unidentified fibrosis can evolve into more severe consequences over a period of time such as cirrhosis and hepatocellular carcinoma. It is well recognized now that in addition to external agents, genetic predisposition also plays a role in the development of liver fibrosis. An improved understanding of the cellular pathways of fibrosis can illuminate our understanding of this process, and uncover potential therapeutic targets. Here we summarized recent aspects in the understanding of relevant pathways, cellular and molecular drivers of hepatic fibrosis and discuss how this knowledge impact the therapy of respective disease.
TL;DR: A comprehensive review of the antibacterial potential of plants has never before been attempted as mentioned in this paper, where the authors identified a total of 6,083 articles published between 1946 and 2019 and then reviewed 66% of these (4,024) focusing on articles published from 2012 to 2019.
Abstract: Background: Antimicrobial resistance represents a serious threat to human health across the globe. The cost of bringing a new antibiotic from discovery to market is high and return on investment is low. Furthermore, the development of new antibiotics has slowed dramatically since the 1950s' golden age of discovery. Plants produce a variety of bioactive secondary metabolites that could be used to fuel the future discovery pipeline. While many studies have focused on specific aspects of plants and plant natural products with antibacterial properties, a comprehensive review of the antibacterial potential of plants has never before been attempted. Objectives: This systematic review aims to evaluate reports on plants with significant antibacterial activities. Methods: Following the PRISMA model, we searched three electronic databases: Web of Science, PubMed and SciFinder by using specific keywords: "plant," "antibacterial," "inhibitory concentration." Results: We identified a total of 6,083 articles published between 1946 and 2019 and then reviewed 66% of these (4,024) focusing on articles published between 2012 and 2019. A rigorous selection process was implemented using clear inclusion and exclusion criteria, yielding data on 958 plant species derived from 483 scientific articles. Antibacterial activity is found in 51 of 79 vascular plant orders throughout the phylogenetic tree. Most are reported within eudicots, with the bulk of species being asterids. Antibacterial activity is not prominent in monocotyledons. Phylogenetic distribution strongly supports the concept of chemical evolution across plant clades, especially in more derived eudicot families. The Lamiaceae, Fabaceae and Asteraceae were the most represented plant families, while Cinnamomum verum, Rosmarinus vulgaris and Thymus vulgaris were the most studied species. South Africa was the most represented site of plant collection. Crude extraction in methanol was the most represented type of extraction and leaves were the main plant tissue investigated. Finally, Staphylococcus aureus was the most targeted pathogenic bacteria in these studies. We closely examine 70 prominent medicinal plant species from the 15 families most studied in the literature. Conclusion: This review depicts the current state of knowledge regarding antibacterials from plants and provides powerful recommendations for future research directions.
TL;DR: In this paper, the concentrations of five heavy metals cadmium (Cd), lead (Pb), arsenic (As), mercury (Hg) and copper (Cu) were investigated using Inductively Coupled Plasma Optical Mass Spectrometry (ICP-MS) with 1773 samples around the world.
Abstract: Heavy metal contamination in herbal medicines is a global threat to human beings especially at levels above known threshold concentrations. The concentrations of five heavy metals cadmium (Cd), lead (Pb), arsenic (As), mercury (Hg) and copper (Cu) were investigated using Inductively Coupled Plasma Optical Mass Spectrometry (ICP-MS) with 1773 samples around the world. According to Chinese Pharmacopoeia, 30.51% (541) samples were detected with at least one over-limit metal. The over-limit ratio for Pb was 5.75% (102), Cd at 4.96% (88), As at 4.17% (74), Hg at 3.78% (67), and of Cu, 1.75% (31). For exposure assessment, Pb, Cd, As, and Hg have resulted in higher than acceptable risks in 25 kinds of herbs. The maximal Estimated Daily Intake of Pb in seven herbs, of Cd in five, of Hg in four, and As in three exceeded their corresponding Provisional Tolerable Daily Intakes. In total 25 kinds of herbs present an unacceptable risk as assessed with the Hazard Quotient or Hazard Index. Additionally, the carcinogenic risks were all under acceptable limits. Notably, As posed the highest risk in all indicators including Estimated Daily Intake, Hazard Index, and carcinogenic risks. Therefore further study on enrichment effect of different states of As and special attention to monitoring shall be placed on As related contamination.
TL;DR: In this article, a review summarizes the recent advances of important cancer-related ABC transporters, focusing on their physiological functions, structures, and the development of new compounds as ABC transporter inhibitors.
Abstract: Multiple drug resistance (MDR), referring to the resistance of cancer cells to a broad spectrum of structurally and mechanistically unrelated drugs across membranes, severely impairs the response to chemotherapy and leads to chemotherapy failure. Overexpression of ATP binding cassette (ABC) transporters is a major contributing factor resulting in MDR, which can recognize and mediate the efflux of diverse drugs from cancer cells, thereby decreasing intracellular drug concentration. Therefore, modulators of ABC transporter could be used in combination with standard chemotherapeutic anticancer drugs to augment the therapeutic efficacy. This review summarizes the recent advances of important cancer-related ABC transporters, focusing on their physiological functions, structures, and the development of new compounds as ABC transporter inhibitors.
TL;DR: A review of the role of the NLRP3 inflammasome in the pathogenesis of neurodegenerative diseases can be found in this article, where the authors discuss the potential of inhibition of the inflammmasome as a potential future therapy.
Abstract: The prevalence of neurodegenerative disease has increased significantly in recent years, and with a rapidly aging global population, this trend is expected to continue. These diseases are characterised by a progressive neuronal loss in the brain or peripheral nervous system, and generally involve protein aggregation, as well as metabolic abnormalities and immune dysregulation. Although the vast majority of neurodegeneration is idiopathic, there are many known genetic and environmental triggers. In the past decade, research exploring low-grade systemic inflammation and its impact on the development and progression of neurodegenerative disease has increased. A particular research focus has been whether systemic inflammation arises only as a secondary effect of disease or is also a cause of pathology. The inflammasomes, and more specifically the NLRP3 inflammasome, a crucial component of the innate immune system, is usually activated in response to infection or tissue damage. Dysregulation of the NLRP3 inflammasome has been implicated in the progression of several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion diseases. This review aims to summarise current literature on the role of the NLRP3 inflammasome in the pathogenesis of neurodegenerative diseases, and recent work investigating NLRP3 inflammasome inhibition as a potential future therapy.
TL;DR: In this paper, the authors discuss novel treatment target agents including selective janus kinase (JAK) inhibitors, anti-interleukin (IL) (IL-12/IL-23), leukocyte trafficking/migrating inhibitors (such as sphingosine-1-phosphate receptor modulator) and other small molecules currently in development.
Abstract: Inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease are chronic, relapsing and remitting disorders of intestinal inflammation with potential systemic manifestations. Despite the availability of current biologics, such as anti-tumor necrosis factor (anti-TNF), anti-integrins, anti-interleukins and small molecules such as tofacitinib, the rates of primary and secondary treatment failure remain high in IBD. This highlights the importance of continued development of new therapeutic targets and modifications of existing ones to improve the treatment response rates and to also improve the safety profile and tolerability of these medications. In this review we will discuss novel treatment target agents including selective janus kinase (JAK) inhibitors, anti-interleukin (IL) (IL-12/IL-23), leukocyte trafficking/migrating inhibitors (such as sphingosine-1-phosphate receptor modulator) and other small molecules currently in development.
TL;DR: In this paper, the authors reviewed the mechanism and application of PD1/PDL1 checkpoint inhibitors in tumor immunotherapy and further reflect on the effectiveness of the treatment and the side effects it brings.
Abstract: Programmed death protein 1 (PD1) is a common immunosuppressive member on the surface of T cells and plays an imperative part in downregulating the immune system and advancing self-tolerance. Its ligand programmed cell death ligand 1 (PDL1) is overexpressed on the surface of malignant tumor cells, where it binds to PD1, inhibits the proliferation of PD1-positive cells, and participates in the immune evasion of tumors leading to treatment failure. The PD1/PDL1-based pathway is of great value in immunotherapy of cancer and has become an important immune checkpoint in recent years, so understanding the mechanism of PD1/PDL1 action is of great significance for combined immunotherapy and patient prognosis. The inhibitors of PD1/PDL1 have shown clinical efficacy in many tumors, for example, blockade of PD1 or PDL1 with specific antibodies enhances T cell responses and mediates antitumor activity. However, some patients are prone to develop drug resistance, resulting in poor treatment outcomes, which is rooted in the insensitivity of patients to targeted inhibitors. In this paper, we reviewed the mechanism and application of PD1/PDL1 checkpoint inhibitors in tumor immunotherapy. We hope that in the future, promising combination therapy regimens can be developed to allow immunotherapeutic tools to play an important role in tumor treatment. We also discuss the safety issues of immunotherapy and further reflect on the effectiveness of the treatment and the side effects it brings.
Shahid Beheshti University of Medical Sciences and Health Services1, Presidency University, Kolkata2, Kathmandu3, Lahore College for Women University4, Mohammed V University5, Ilia State University6, State University of Campinas7, University of Concepción8, Semnan University9, University of Medicine and Pharmacy of Craiova10, University of Zaragoza11, Carol Davila University of Medicine and Pharmacy12
TL;DR: The genus Cinnamomum includes a number of plant species largely used as food, food additives and spices for a long time as mentioned in this paper and different traditional healing systems have used these plants as herbal remedies to cure diverse ailments.
Abstract: The genus Cinnamomum includes a number of plant species largely used as food, food additives and spices for a long time. Different traditional healing systems have used these plants as herbal remedies to cure diverse ailments. The aim of this comprehensive and updated review is to summarize the biodiversity of the genus Cinnamomum, its bioactive compounds, the mechanisms that underlie the pharmacological activities and molecular targets and toxicological safety. All the data in this review have been collected from databases and recent scientific literature including Web of Science, PubMed, ScienceDirect etc. The results showed that the bioactive compounds of Cinnamomum species possess antimicrobial, antidiabetic, antioxidant, anti-inflammatory, anticancer and neuroprotective effects. The preclinical (in vitro/in vivo) studies provided the possible molecular mechanisms of these action. As a novelty, recent clinical studies and toxicological data described in this paper support and confirm the pharmacological importance of the genus Cinnamomum. In conclusion, the obtained results from preclinical studies and clinical trials, as well as reduced side effects provide insights into future research of new drugs based on extracts and bioactive compounds from Cinnamomum plants.
TL;DR: In this paper, the LASSO algorithm was used to build the risk signature, and the prediction model was evaluated by the survival analysis and receiver operating characteristic curve of LUAD.
Abstract: Background: Lung cancer has emerged as one of the most common cancers in recent years. The mitochondrial electron transport chain (ETC) is closely connected with metabolic pathways and inflammatory response. However, the influence of ETC-associated genes on the tumor immune response and the pathogenesis of lung cancer is not clear and needs further exploration. Methods: The RNA-sequencing transcriptome and clinical characteristic data of LUAD were downloaded from the Cancer Genome Atlas (TCGA) database. The LASSO algorithm was used to build the risk signature, and the prediction model was evaluated by the survival analysis and receiver operating characteristic curve. We explored the function of FDX1 through flow cytometry, molecular biological methods, and liquid chromatography-tandem mass spectrometry/mass spectrometry (LC-MS/MS). Results: 12 genes (FDX1, FDX2, LOXL2, ASPH, GLRX2, ALDH2, CYCS, AKR1A1, MAOB, RDH16, CYBB, and CYB5A) were selected to build the risk signature, and the risk score was calculated with the coefficients from the LASSO algorithm. The 1-year, 3-year, and 5-year area under the curve (AUC) of ROC curves of the dataset were 0.7, 0.674, and 0.692, respectively. Univariate Cox analysis and multivariate Cox regression analysis indicated that the risk signature is an independent risk factor for LUAD patients. Among these genes, we focused on the FDX1 gene, and we found that knockdown of FDX1 neither inhibited tumor cell growth nor did it induce apoptosis or abnormal cell cycle distribution. But FDX1 could promote the ATP production. Furthermore, our study showed that FDX1 was closely related to the glucose metabolism, fatty acid oxidation, and amino acid metabolism. Conclusion: Collectively, this study provides new clues about carcinogenesis induced by ETC-associated genes in LUAD and paves the way for finding potential targets of LUAD.
TL;DR: In this paper, the authors provide consolidated information on currently available diagnosis and treatment options for invasive breast cancer(s) (breast cancer) at some point in their lifetime, including mammography, ultrasound, and some high-end molecular bioimaging.
Abstract: The International Agency for Research on Cancer (IARC) has recently reported a 66% increase in the global number of cancer deaths since 1960. In the US alone, about one in eight women is expected to develop invasive breast cancer(s) (breast cancer) at some point in their lifetime. Traditionally, a BC diagnosis includes mammography, ultrasound, and some high-end molecular bioimaging. Unfortunately, these techniques detect BC at a later stage. So early and advanced molecular diagnostic tools are still in demand. In the past decade, various histological and immuno-molecular studies have demonstrated that BC is highly heterogeneous in nature. Its growth pattern, cytological features, and expression of key biomarkers in BC cells including hormonal receptor markers can be utilized to develop advanced diagnostic and therapeutic tools. A cancer cell's progression to malignancy exhibits various vital biomarkers, many of which are still underrepresented in BC diagnosis and treatment. Advances in genetics have also enabled the development of multigene assays to detect genetic heterogeneity in BC. However, thus far, the FDA has approved only four such biomarkers-cancer antigens (CA); CA 15-3, CA 27-29, Human epidermal growth factor receptor 2 (HER2), and circulating tumor cells (CTC) in assessing BC in body fluids. An adequately structured portable-biosensor with its non-invasive and inexpensive point-of-care analysis can quickly detect such biomarkers without significantly compromising its specificity and selectivity. Such advanced techniques are likely to discriminate between BC and a healthy patient by accurately measuring the cell shape, structure, depth, intracellular and extracellular environment, and lipid membrane compositions. Presently, BC treatments include surgery and systemic chemo- and targeted radiation therapy. A biopsied sample is then subjected to various multigene assays to predict the heterogeneity and recurrence score, thus guiding a specific treatment by providing complete information on the BC subtype involved. Thus far, we have seven prognostic multigene signature tests for BC providing a risk profile that can avoid unnecessary treatments in low-risk patients. Many comparative studies on multigene analysis projected the importance of integrating clinicopathological information with genomic-imprint analysis. Current cohort studies such as MINDACT, TAILORx, Trans-aTTOM, and many more, are likely to provide positive impact on long-term patient outcome. This review offers consolidated information on currently available BC diagnosis and treatment options. It further describes advanced biomarkers for the development of state-of-the-art early screening and diagnostic technologies.