scispace - formally typeset
Search or ask a question

Showing papers in "Current Medicinal Chemistry in 2021"


Journal ArticleDOI
TL;DR: The literature published on the use of flavonoids in medicine during the past decade was surveyed, their pharmacological activities as well as associated mechanisms of action against variety of health disorders including chronic inflammation, cancer, cardiovascular complications and hypoglycemia were documented.
Abstract: Flavonoids, commonly found in various plants, are a class of polyphenolic compounds having a basic structural unit of 2-phenylchromone. Flavonoid compounds have attracted much attention due to their wide biological applications. In order to facilitate further research on the biomedical application of flavonoids, we surveyed the literature published on the use of flavonoids in medicine during the past decade, documented the commonly found structures in natural flavonoids, and summarized their pharmacological activities as well as associated mechanisms of action against a variety of health disorders including chronic inflammation, cancer, cardiovascular complications and hypoglycemia. In this mini-review, we provide suggestions for further research on the biomedical applications of flavonoids.

84 citations


Journal ArticleDOI
TL;DR: In this article, the authors summarized the recent achievements of ZIF-8 for biomedical applications, such as cancer therapy, antimicrobial, biosensing, and biocatalysis.
Abstract: Beyond being an excellent protective material for bioentities, zeolitic imidazolate frameworks (ZIF-8) have advanced several applications, including biomedical applications. The straightforward synthesis of ZIF-8 at mild conditions improved the biomineralization of several biomolecules, e.g., protein, peptides, carbohydrate, and biological cells, such as viruses and bacterial cells. Bioinspiration of ZIF-8 enhanced and improved the material's applications for biomedicine. This review article summarized the recent achievements of ZIF-8 for biomedical applications, such as cancer therapy, antimicrobial, biosensing, and biocatalysis. ZIF8-based materials advanced cancer therapy via drug delivery of chemotherapeutic drugs, photothermal therapy (PTT), photodynamic therapy (PDT), hemodynamic therapy (CDT), gene therapy, and starvation therapy. Antibacterial agent encapsulated ZIF-8 exhibited superior biological activity compared to the free antibacterial agents. ZIF-8 based materials enhanced the selectivity and sensitivity for analytes' biosensing, ensuring their potential for electronic devices. Biocatalysis of enzyme encapsulated ZIF-8 offered high catalytic performance with robust properties for recycling. ZIF-8 acts as a protective host for enzymes, proteins, and drugs from degradation induced due to temperature, solvents, and proteolytic agents. The first part of the review discussed the structure, chemistry, and bioinspiration of ZIF-8. The second part reviewed the biomedical applications of ZIF-8. The potential risks and current challenges of using ZIF-8 for biomedical applications were also reviewed.

77 citations


Journal ArticleDOI
TL;DR: The molecular mechanisms of osteoporosis, current drugs for osteop orosis treatment, and new drug development strategies are summarized to provide an alternative approach.
Abstract: CDATA[Osteoporosis is a pathological loss of bone mass due to an imbalance in bone remodeling where osteoclast-mediated bone resorption exceeds osteoblast-mediated bone formation resulting in skeletal fragility and fractures. Anti-resorptive agents, such as bisphosphonates and SERMs, and anabolic drugs that stimulate bone formation, including PTH analogues and sclerostin inhibitors, are current treatments for osteoporosis. Despite their efficacy, severe side effects and loss of potency may limit the long term usage of a single drug. Sequential and combinational use of current drugs, such as switching from an anabolic to an anti-resorptive agent, may provide an alternative approach. Moreover, there are novel drugs being developed against emerging new targets such as Cathepsin K and 17β-HSD2 that may have less side effects. This review will summarize the molecular mechanisms of osteoporosis, current drugs for osteoporosis treatment, and new drug development strategies.

69 citations


Journal ArticleDOI
TL;DR: Targeting of CSCs with phytotochemicals such as curcumin, EGCG, sulforaphane, resveratrol and genistein, combined with each other and/or in combination with conventional cytotoxic drugs and novel cancer therapeutics, may offer a novel therapeutic strategy against cancer.
Abstract: Cancer stem cells (CSCs) constitute a subpopulation of tumor cells that possess self-renewal and tumor initiation capacity, and the ability to give rise to the heterogeneous lineages of cancer cells that comprise the tumor. CSCs exhibit intrinsic mechanisms of resistance to virtually all conventional cancer therapeutics, allowing them to survive current cancer therapies and to initiate tumor recurrence and metastasis. Different pathways and mechanisms that confer resistance and survival of CSCs, including activation of the Wnt/β- catenin, Sonic Hedgehog, Notch, PI3K/Akt/mTOR and STAT3 signaling pathways, expression of aldehyde dehydrogenase 1 (ALDH1) and oncogenic microRNAs, and acquisition of epithelial-mesenchymal transition (EMT), have been identified recently. Certain phytochemicals, in particular curcumin, epigallocatechin-3-gallate (EGCG), sulforaphane, resveratrol and genistein have been shown to interfere with these intrinsic CSC pathways in vitro and in human xenograft mice, leading to elimination of CSCs. Moreover, recent clinical trials have demonstrated the therapeutic efficacy of five phytochemicals, alone or in combination with modern cancer therapeutics, and in various types of cancer. Since current cancer therapies fail to eradicate CSCs, leading to cancer recurrence and progression, targeting of CSCs with phytochemicals such as curcumin, EGCG, sulforaphane, resveratrol and genistein, combined with each other and/or in combination with conventional cytotoxic drugs and novel cancer therapeutics, may offer a novel therapeutic strategy against cancer.

45 citations


Journal ArticleDOI
TL;DR: The main objective is to make a contribution to the comprehension of what is currently ready for anti-SARS-CoV-2 prophylactic intervention, as well as to provide the reader with an overall picture of the most innovative approaches for the development of vaccines that could be of general utility in the fight against the most pathogenic Coronaviruses.
Abstract: The aim of this review article is to summarize the knowledge available to date on prophylaxis achievements to fight against Coronavirus. This work will give an overview of what is reported in the most recent literature on vaccines (under investigation or already developed like BNT162b2, mRNA-1273, and ChAdOx1-S) effective against the most pathogenic Coronaviruses (SARS-CoV-1, MERS-CoV-1, and SARS-CoV-2), with of course particular attention paid to those under development or already in use to combat the current COVID-19 (COronaVIrus Disease 19) pandemic. Our main objective is to make a contribution to the comprehension, additionally at a molecular level, of what is currently ready for anti-SARS-CoV-2 prophylactic intervention, as well as to provide the reader with an overall picture of the most innovative approaches for the development of vaccines that could be of general utility in the fight against the most pathogenic Coronaviruses.

41 citations


Journal ArticleDOI
TL;DR: This study investigates the existing approaches from multiple perspectives to find out which deep network architectures are utilized to extract features from drug compound and protein sequences and the process of how to combine descriptors for drug and protein features.
Abstract: Drug-target Interactions (DTIs) prediction plays a central role in drug discovery. Computational methods in DTIs prediction have gained more attention because carrying out in vitro and in vivo experiments on a large scale is costly and time-consuming. Machine learning methods, especially deep learning, are widely applied to DTIs prediction. In this study, the main goal is to provide a comprehensive overview of deep learning-based DTIs prediction approaches. Here, we investigate the existing approaches from multiple perspectives. We explore these approaches to find out which deep network architectures are utilized to extract features from drug compound and protein sequences. Also, the advantages and limitations of each architecture are analyzed and compared. Moreover, we explore the process of how to combine descriptors for drug and protein features. Likewise, a list of datasets that are commonly used in DTIs prediction is investigated. Finally, current challenges are discussed and a short future outlook of deep learning in DTI prediction is given.

37 citations


Journal ArticleDOI
TL;DR: The chemistry and most known toxic effects of CsA including the nephrotoxic, hepatotoxic, neurotoxic and cardiotoxic effects are summarized and its available toxicity data (different species, different routes) published formerly are summarized.
Abstract: 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.

32 citations


Journal ArticleDOI
TL;DR: The association of obesity and insulin resistance with chronic inflammation, genetic, and epigenetic factors is described and there is evidence of associations between a genetic predisposition to obesity in children with elevated levels of certain miRNAs.
Abstract: BACKGROUND Obesity is known to be a multifactorial disease. In its pathogenesis, different factors such as chronic inflammation, oxidative stress, insulin resistance, genetic factors, environmental effects, vegetative disturbance, and unbalanced nutrition play a significant role. METHODOLOGY This study describes the association of obesity and insulin resistance with chronic inflammation, genetic, and epigenetic factors. Previous literature has been reviewed to explain the relation of obesity with those factors involved in chronic low-grade inflammation and insulin. RESULTS Obesity is associated with a decrease in ghrelin secretion, elevated plasma leptin levels, oxidative stress, increased macrophage phagocytic activity, and the induction of proinflammatory synthesis of cytokines and interferon-gamma. Obesity is linked to decreased levels of cytochrome P450 (CYP) enzymes and impaired detoxification processes. Deficiency of vitamins and minerals can also play a significant role in the development of oxidative stress and chronic inflammation in obesity. There is evidence of associations between a genetic predisposition to obesity in children with elevated levels of certain miRNAs. CONCLUSION The purpose of the present review is an analysis of the multiple factors associated with obesity.

30 citations


Journal ArticleDOI
TL;DR: In this paper, a drug-repositioning pipeline was proposed for the design and discovery of an effective fungal-derived bioactive metabolite as a drug candidate against SARS-CoV-2.
Abstract: Background SARS-CoV-2, which emerged in Wuhan, China, is a new global threat that has killed millions of people and continues to do so. This pandemic has not only threatened human life but has also triggered economic downturns across the world. Researchers have made significant strides in discovering molecular insights into SARS-CoV-2 pathogenesis and developing vaccines, but there is still no successful cure for SARS-CoV-2 infected patients. Objective The present study has proposed a drug-repositioning pipeline for the design and discovery of an effective fungal-derived bioactive metabolite as a drug candidate against SARS-CoV-2. Methods Fungal derivative "Cordycepin" was selected for this study to investigate the inhibitory properties against RNA-dependent RNA polymerase (RdRp) (PDB ID: 6M71) of SARS-CoV-2. The pharmacological profile, intermolecular interactions, binding energy, and stability of the compound were determined utilizing cheminformatic approaches. Subsequently, molecular dynamic simulation was performed to better understand the binding mechanism of cordycepin to RdRp. Results The pharmacological data and retrieved molecular dynamics simulations trajectories suggest excellent drug-likeliness and greater structural stability of cordycepin, while the catalytic residues (Asp760, Asp761), as well as other active site residues (Trp617, Asp618, Tyr619, Trp800, Glu811) of RdRp, showed better stability during the overall simulation span. Conclusion Promising results of pharmacological investigation along with molecular simulations revealed that cordycepin exhibited strong inhibitory potential against SARS-CoV-2 polymerase enzyme (RdRp). Hence, cordycepin should be highly recommended to test in a laboratory to confirm its inhibitory potential against the SARS-CoV-2 polymerase enzyme (RdRp).

30 citations


Journal ArticleDOI
TL;DR: The review mainly concentrated on recently identified natural products and derivatives as COX-2 inhibitors, the characteristics of their structural core scaffolds, their anti-inflammatory effects, molecular mechanisms for enzymatic inhibition and related structure-activity relationships, and the utilization of these natural remedies in future cancer prevention.
Abstract: COX-2, a key enzyme that catalyzed the rate-limiting steps in the conversion of arachidonic acid to prostaglandins, played a pivotal role in the inflammatory process. Different from other family members, COX-2 was barely detectable in normal physiological conditions and highly inducible during the acute inflammatory response of human bodies to injuries or infections. Therefore, the therapeutic utilization of selective COX-2 inhibitors has already been considered as an effective approach for the treatment of inflammation with diminished side effects. Currently, both traditional and newer NSAIDs are the commonly prescribed medications that treat inflammatory diseases by targeting COX-2. However, due to the cardiovascular side-effects of the NSAIDs, finding reasonable alternatives for these frequently prescribed medicines are a hot spot in medicinal chemistry research. Naturallyoccurring compounds have been reported to inhibit COX-2, thereby possessing beneficial effects against inflammation and certain cell injury. The review mainly concentrated on recently identified natural products and derivatives as COX-2 inhibitors, the characteristics of their structural core scaffolds, their anti-inflammatory effects, molecular mechanisms for enzymatic inhibition, and related structure-activity relationships. According to the structural features, the natural COX-2 inhibitors were mainly divided into the following categories: natural phenols, flavonoids, stilbenes, terpenoids, quinones, and alkaloids. Apart from the anti-inflammatory activities, a few dietary COX-2 inhibitors from nature origin also exhibited chemopreventive effects by targeting COX-2-mediated carcinogenesis. The utilization of these natural remedies in future cancer prevention was also discussed. In all, the survey on the characterized COX-2 inhibitors from natural sources paves the way for the further development of more potent and selective COX-2 inhibitors in the future.

30 citations


Journal ArticleDOI
TL;DR: The mechanisms that illustrate the relationship between hyperpermeability, the composition of the gut microbiota, and obesity will be discussed.
Abstract: Intestinal hyperpermeability is a complex metabolic process mediated by different pathways in close relation to the gut microbiota. Previous studies suggested that the gut microbiota is involved in different metabolic regulations, and its imbalance is associated with several metabolic diseases, including obesity. It is well known that intestinal hyperpermeability is associated with dysbiosis, and the combination of these two conditions can lead to an increase in the level of low-grade inflammation in obese patients due to an increase in pro-inflammatory cytokine levels. Inflammatory bowel syndrome often accompanies this condition causing an alteration of the intestinal mucosa and thus reinforcing the dysbiosis and gut hyperpermeability. The onset of metabolic disorders depends on violations of the integrity of the intestinal barrier as a result of increased intestinal permeability. Chronic inflammation due to endotoxemia is responsible for the development of obesity. Metabolic disorders are associated with dysregulation of the microbiota-gut-brain axis and with an altered composition of gut flora. In this review, we will discuss the mechanisms that illustrate the relationship between hyperpermeability, the composition of the gut microbiota, and obesity.

Journal ArticleDOI
TL;DR: It is evident that cytokines play a central regulatory role in the inflammatory process and immune cell response that underlies bone destruction in periodontitis and specific cytokine targeting should be considered as a complementary therapeutic scheme to current periodontal management.
Abstract: BACKGROUND Periodontitis is an immune-inflammatory disease that leads to the progressive destruction of bone and connective tissue in the periodontal area. The cytokine network plays a primary role in tissue homeostasis, the recruitment of immune cells to control the pathogenic impact and the regulation of osteoclastic function, thus modulating the intensity and duration of the immune response. This review provides an update on the main cytokines implicated in the pathogenesis and progression of periodontitis and their targeting potential in order to enrich current treatment options. METHODS A structured search of bibliographic databases (PubMed, MEDLINE, Scopus) was performed for peer-reviewed cytokine studies focused on periodontitis the last ten years. A qualitative content analysis was performed in screened papers and a critical discussion of main findings is provided. RESULTS An altered cytokine profile has been detected in periodontitis patients and the interplay of pro-inflammatory and/or anti-inflammatory cytokines has been associated with disease pathogenesis. Among the most prominent pro-inflammatory cytokines, TNF-α, IL-1β, IL-17, IL-6 and the chemokines CXCL-6, CXCL-8 are overexpressed in periodontitis patients and correlate with disease progression. On the other hand, the anti-inflammatory IL-4 and IL- 11 levels are reduced while IL-12 and IFN-γ expression play a dual role in periodontal disease. Current periodontitis treatment strategies include selective antibiotics, antimicrobial photodynamic therapy and probiotics, which can modulate the cytokine network and when applied in combination with specific anti-cytokine agents can exert additional beneficial effects. CONCLUSION It is evident that cytokines play a central regulatory role in the inflammatory process and immune cell response that underlies bone destruction in periodontitis. Specific cytokine targeting should be considered as a complementary therapeutic scheme to current periodontal management.

Journal ArticleDOI
TL;DR: The emergences of modern methods especially that based on transition metal catalysed reactions have opened up tremendous opportunities in the area of indole synthesis for the identification of potent and promising agents to fight against MTB.
Abstract: Background The indole framework is considered as one of the privileged structures in the area of medicinal chemistry and drug discovery because compounds containing this framework have shown to possess a remarkable ability to bind with many receptors or proteins with high affinity. It is therefore not surprising that the indole nucleus is a frequently found moiety in many bioactive agents or drugs. Indole derivatives have also been explored or studied for their anti-tubercular properties for a long time. The growth inhibition of Mycobacterium tuberculosis (MTB) in vitro and in vivo by the gut microbiota metabolite indole propionic acid (IPA) is one of the recent examples. Notably, tuberculosis (TB), an intractable disease and a major cause of death worldwide, has caused an alarming rise in the number of TB cases recently because of two main reasons, i.e., a several-fold rise among HIV-infected patients and increased drug resistance by some bacterial strains. Thus, the identification of new agents or potential drugs against TB is urgently needed. Methods While the specific pharmacological target or mechanism of action (MOA) for antitubercular activities has been reported for many indole derivatives, the MOA is not well defined or known for a number of indole derivatives though they were found to be active against MTB. In the current review article, we have focused on both types of indole derivatives that have shown activities against MTB. The indoles with known MOA are further segregated based on this pharmacological target reported or indicated whereas other indoles are classified based on the type of anti-TB properties shown by them. The literature for the last 20 years as well as related to up to date knowledge and information was searched on Pubmed, Google Scholar, MEDLINE, and various other databases until August 2020. Results A diverse range of functionalized indole derivatives, such as indole-based alkaloids, simple indoles, fused indoles, amide/peptide derivatives of indole, isatin derivatives, etc., have been reported to possess anti-tubercular activities. The anti-tubercular activities, in silico studies (if reported) and the chemical syntheses (in most of the cases) of representative indole derivatives are presented briefly in the current article. The papers referenced by this review allow a deep analysis of the status of the indole-based anti-tubercular agents explored over the past two decades. Conclusion This review aims at stimulating renewed interest and effort in the discovery and development of new indole-based agents or potential drugs for the treatment of TB. The emergence of modern methods, especially those based on transition metal-catalyzed reactions, has opened up tremendous opportunities in the area of indole synthesis. The desired goal would be to have utilized these modern methodologies for the identification of potent and promising agents to fight against MTB.

Journal ArticleDOI
TL;DR: The Jak/STAT signal transduction pathway in the pathogenesis of breast cancer, and the potential for the application of JAK/STAT inhibitors in breast cancer treatment are discussed.
Abstract: Breast cancer is the most common malignant tumor in women worldwide. Traditional ways of treatment, including radiotherapy and endocrine therapy, for breast cancer have inevitable side effects. In recent decades, targeted therapies for breast cancer have rapidly advanced and shown a promising future. The JAK/STAT signaling pathway has been shown to play important roles in tumorigenesis, maintenance and metastasis of breast cancer. Hence, many small molecule inhibitors of JAK and STAT proteins have been developed. These inhibitors exhibit potent inhibitory effects on breast cancer in both cellular and animal models, and even some of them have already been in clinical trials. This review article discussed the JAK/STAT signal transduction pathway in the pathogenesis of breast cancer, and the potential for the application of JAK/STAT inhibitors in breast cancer treatment.

Journal ArticleDOI
TL;DR: Current NAR formulations seem to improve its bioavailability, which would allow its clinical application, and the evidence of the NAR action on the gastrointestinal tract is reported as well as its influence on the microbiota composition and activity.
Abstract: Background Naringin (NAR) is a flavonoid enriched in several medicinal plants and fruits. An increasing interest in this molecule has emerged because it has the potential to contribute to alleviating many health problems. Objective This review briefly describes the NAR pharmacokinetics and it mainly focuses on the in vitro and in vivo animal studies showing NAR beneficial effects on cardiovascular, metabolic, neurological and pulmonary disorders and cancer. The anabolic effects of NAR on different models of bone and dental diseases are also analyzed. In addition, the evidence of the NAR action on the gastrointestinal tract is reported as well as its influence on the microbiota composition and activity. Finally, current research on NAR formulations and clinical applications are discussed. Methods The PubMed database was searched until 2019, using the keywords NAR, naringenin, cardiovascular and metabolic disorders, neurological and pulmonary disorders, cancer, bone and dental diseases, gastrointestinal tract, microbiota, NAR formulations, clinical trials. Results The number of studies related to the bioavailability and pharmacokinetics of NAR is limited. Positive effects of NAR have been reported on cardiovascular diseases, Type 2 Diabetes Mellitus (T2DM), metabolic syndrome, pulmonary disorders, neurodegenerative diseases, cancer, and gastrointestinal pathologies. The current NAR formulations seem to improve its bioavailability, which would allow its clinical applications. Conclusion NAR is endowed with broad biological effects that could improve human health. Since a scarce number of clinical studies have been performed, the NAR use requires more investigation in order to know better their safety, efficacy, delivery, and bioavailability in humans.

Journal ArticleDOI
TL;DR: A systematic search was conducted on PubMed in December 2019, resulting in 230 publications obtained with the following search query: "Machine Learning" "AND" "Parkinson Disease".
Abstract: Background Parkinson's disease is the second most frequent neurodegenerative disorder. Its diagnosis is challenging and mainly relies on clinical aspects. At present, no biomarker is available to obtain a diagnosis of certainty in vivo. Objective The present review aims at describing machine learning algorithms as they have been variably applied to different aspects of Parkinson's disease diagnosis and characterization. Methods A systematic search was conducted on PubMed in December 2019, resulting in 230 publications obtained with the following search query: "Machine Learning" "AND" "Parkinson Disease". Results the obtained publications were divided into 6 categories, based on different application fields: "Gait Analysis - Motor Evaluation", "Upper Limb Motor and Tremor Evaluation", "Handwriting and typing evaluation", "Speech and Phonation evaluation", "Neuroimaging and Nuclear Medicine evaluation", "Metabolomics application", after excluding the papers of general topic. As a result, a total of 166 articles were analyzed, after elimination of papers written in languages other than English or not directly related to the selected topics. Conclusion Machine learning algorithms are computer-based statistical approaches which can be trained and are able to find common patterns from big amounts of data. The machine learning approaches can help clinicians in classifying patients according to several variables at the same time.

Journal ArticleDOI
TL;DR: Several alkaloids such as galantamine, oridonin, glaucocalyxin B, tetrandrine, berberine, anatabine have been shown anti-inflammatory effects in AD models in vitro as well as in-vivo.
Abstract: Alzheimer's disease (AD) is a chronic neurodegenerative brain disorder characterized by memory impairment, dementia, and oxidative stress in elderly people. Currently, only a few drugs are available in the market with various adverse effects. Therefore, to develop new drugs with protective action against the disease, research is turning to the identification of plant products as a remedy. Natural compounds with anti-inflammatory activity could be good candidates for developing effective therapeutic strategies. Phytochemicals, including Curcumin, Resveratrol, Quercetin, Huperzine-A, Rosmarinic acid, genistein, obovatol, and Oxyresvertarol, were reported molecules for the treatment of AD. Several alkaloids, such as galantamine, oridonin, glaucocalyxin B, tetrandrine, berberine and anatabine, have been shown anti-inflammatory effects in AD models in vitro as well as in-vivo. In conclusion, natural products from plants represent interesting candidates for the treatment of AD. This review highlights the potential of specific compounds from natural products along with their synthetic derivatives to counteract AD in the CNS.

Journal ArticleDOI
TL;DR: The present review focused on the extraction, determination, pharmacokinetics and bioactivity of 1-DNJ, as well as the clinical application of1- DNJ derivatives.
Abstract: 1-Deoxynojirimycin (1-DNJ) is a naturally occurring sugar analogue with unique bioactivities. It is found in mulberry leaves and silkworms, as well as in the metabolites of certain microorganisms, including Streptomyces and Bacillus. 1-DNJ is a potent α-glucosidase inhibitor and it possesses anti-hyperglycemic, anti-obese, anti-viral and anti-tumor properties. Some derivatives of 1-DNJ, like miglitol, miglustat and migalastat, were applied clinically to treat diseases such as diabetes and lysosomal storage disorders. The present review focused on the extraction, determination, pharmacokinetics and bioactivity of 1-DNJ, as well as the clinical application of 1-DNJ derivatives.

Journal ArticleDOI
TL;DR: Blocking or targeting the NFκB-signaling pathways by using natural and synthetic compounds could be a potential mechanism to cure the NF-κB induced tumors.
Abstract: Nuclear Factor-κappa B (NF-κB) is a family of critical transcription factors of the inflammatory pathway and plays an imperative role in the progression of various cancers such as breast, lung, liver, pancreatic, prostate and multiple types of lymphoma. NF- κB develops an inherent relationship between inflammation and cancer. It is a crucial factor that controls the ability of malignant and pre-neoplastic cells to prevent programmed cell death-based tumor-surveillance channels. Due to its high significance in the onset and progression of various cancers, it has become an excellent target for cancer therapy. The emerging targeted therapies provide a lot of hope, whereby a single protein or generally the target enzyme is completely blocked. Several natural compounds have shown anticancer and anti-inflammatory activities by inhibiting the NF-κB pathway in various cancer types. About 750 natural and synthetic inhibitors of the NF-κB have been reported. These inhibitors include microbial and viral proteins, small RNA/DNA, antioxidants, small molecules, peptides, and engineered constitutively active polypeptides, all of which may inhibit canonical and alternative NF-κB pathways. Thus, blocking or targeting the NF-κB-signaling pathways using natural and synthetic compounds could be a potential mechanism to cure the NF-κB induced tumors.

Journal ArticleDOI
TL;DR: In this article, the authors conducted a meta-analysis on endothelial biomarkers related to Coronavirus Disease 2019 severity and found significant heterogeneity in COVID-19 patients, with higher levels of MR-proADM, E-selectin, VCAM-1, Von Willebrand Factor Antigen (VWF-Ag), soluble Thrombomodulin (sTM), and Ang-2 (Ang-2).
Abstract: Background Several studies have revealed the link between Coronavirus Disease 2019 (COVID-19) and endothelial dysfunction. To better understand the global pattern of this relationship, we conducted a meta-analysis on endothelial biomarkers related to COVID-19 severity. Methods We systematically searched the literature up to March 10, 2021, for studies investigating the association between COVID-19 severity and the following endothelial biomarkers: Intercellular Adhesion Molecule 1 (ICAM-1), Vascular Cell Adhesion Molecule 1 (VCAM-1), E-selectin, P-selectin, Von Willebrand Factor Antigen (VWF-Ag), soluble Thrombomodulin (sTM), Mid-regional pro-adrenomedullin (MR-proADM), and Angiopoietin-2 (Ang-2). Pooled estimates and mean differences (PMD) for each biomarker were reported. Results A total of 27 studies (n=2213 patients) were included. Critically ill patients presented with higher levels of MR-proADM (PMD: 0.71 nmol/L, 95% CI: 0.22 to 1.20 nmol/L, p=0.02), E-selectin (PMD: 13,32 pg/ml, 95% CI: 4,89 to 21,75 pg/ml, p=0.008), VCAM-1 (PMD: 479 ng/ml, 95% CI: 64 to 896 ng/ml, p=0.03), VWF-Ag (PMD: 110.5 IU/dl, 95% CI: 44.8 to 176.1 IU/dl, p=0.04) and Ang-2 (PMD: 2388 pg/ml, 95% CI: 1121 to 3655 pg/ml, p=0.003), as compared to non-critically ill ones. ICAM-1, P-selectin and thrombomodulin did not differ between the two groups (p>0.05). Conclusion Endothelial biomarkers display significant heterogeneity in COVID-19 patients, with higher MR-proADM, E-selectin, VCAM-1, VWF-Ag, and Ang-2 levels being associated with increased severity. These findings strengthen the evidence on the key role of endothelial dysfunction in disease progress.

Journal ArticleDOI
TL;DR: In this paper, the authors explore by spectroscopic methods novel features of a thymine-bearing nucleopeptide based on L-diaminopropanoic acid, including conformational aspects as well as its ability to bind proteins.
Abstract: Background Nucleopeptides are chimeric compounds of biomedical importance carrying DNA nucleobases anchored to peptide backbones with ascertained capacity to bind nucleic acids. However, their ability to interact with proteins involved in pathologies of social relevance is a feature that still requires investigation. The worrying situation currently observed worldwide for the COVID-19 pandemic urgently requires the research of novel anti-SARS-CoV-2 molecular weapons, whose discovery can be aided by in silico predictive studies. Objective The aim of this work is to explore by spectroscopic methods novel features of a thymine-bearing nucleopeptide based on L-diaminopropanoic acid, including conformational aspects as well as its ability to bind proteins, starting from bovine serum albumin (BSA) as a model protein. Moreover, in consideration of the importance of targeting viral proteins in the current fight against COVID-19, we evaluated in silico the interaction of the nucleopeptide with some of the most relevant coronavirus protein targets. Methods First, we investigated via circular dichroism (CD) the conformational behaviour of this thymine-bearing nucleopeptide with temperature: we observed CD spectral changes particularly passing from 15 to 35 °C. Scanning Electron Microscopy (SEM) analysis of the nucleopeptide was also conducted on nucleopeptide solid samples. Additionally, CD binding and in silico investigations were performed with BSA as a model protein. In particular, molecular dockings were run using as targets some of the main SARS-CoV-2 proteins. Results The temperature-dependent CD behaviour reflected the three-dimensional rearrangement of the nucleopeptide at different temperatures, with a higher exposure to the solvent of its chromophores at higher temperatures compared to a more stacked structure at low temperature. SEM analysis of nucleopeptide samples in the solid state showed a granular morphology, with a low roughness and some thread structures. Moreover, we found through spectroscopic studies that the modified peptide bound the albumin target by inducing significant changes to the protein secondary structure. Conclusion CD and in silico studies suggested that the nucleopeptide bound the BSA protein with high affinity according to different binding modes, as testified by binding energy scores lower than -11 kcal/mol. Interestingly, a predictive study performed on 3CLpro and other SARS-CoV-2 protein targets suggested the potential ability of the nucleopeptide to bind with good affinity the main protease of the virus and other relevant targets including the RNA-dependent RNA polymerase, especially when complexed with RNA, the papain-like protease, and the coronavirus helicase at the nucleic acid binding site.

Journal ArticleDOI
TL;DR: The recent development of JNK inhibitors including ATP competitive and ATP non-competitive (allosteric) inhibitors, bidentate-binding inhibitors and dual inhibitors, the challenges, and future direction of J NK inhibitors as potential therapeutic agents are described.
Abstract: c-Jun N-Terminal Kinases (JNKs), members of the Mitogen-Activated Protein Kinase (MAPK) signaling pathway, play a key role in the pathogenesis of many diseases including cancer, inflammation, Parkinson's disease, Alzheimer's disease, cardiovascular disease, obesity, and diabetes. Therefore, JNKs represent new and excellent target by therapeutic agents. Many JNK inhibitors based on different molecular scaffolds have been discovered in the past decade. However, only a few of them have advanced to clinical trials. The major obstacle for the development of JNK inhibitors as therapeutic agents is the JNKisoform selectivity. In this review, we describe the recent development of JNK inhibitors, including ATP competitive and ATP non-competitive (allosteric) inhibitors, bidentatebinding inhibitors and dual inhibitors, the challenges, and the future direction of JNK inhibitors as potential therapeutic agents.

Journal ArticleDOI
TL;DR: This review systematically summarized the paracrine effects of exosomes derived from MSCs and chondrocytes on cartilage regeneration, the use ofExosomes as a delivery vehicle for OA treatment, the effectiveness of such treatments in OA animal models, and future perspective of exOSome-mediated drug delivery as a cell-free therapy of OA.
Abstract: Osteoarthritis (OA) is a degenerative disease of cartilage and bones, which results in severely compromised quality of life in the aged population. However, currently no ideal treatment strategies have been developed to prevent the OA progression. Cell therapies such as chondrocyte and MSC transplantation have been extensively tested and evaluated in clinical trials. Yet, until to date, the clinical efficacy of articular injection of stem cells in OA has not been convincingly demonstrated. Recent studies have indicated that exosomes, one type of Extracellular Vesicles (EVs) play an important regulatory role in the pathogenesis of OA, suggesting the prospective therapeutic application of exosomes in OA treatment. In this review, we systematically summarized the paracrine effects of exosomes derived from MSCs and chondrocytes on cartilage regeneration, the use of exosomes as a delivery vehicle for OA treatment, the effectiveness of such treatments in OA animal models, and future perspective of exosome-mediated drug delivery as a cell-free therapy of OA.

Journal ArticleDOI
TL;DR: The expression and roles of the PD-L1/ PD-1 axis in the progression of cervical cancer provide great potential for using PD- L1/PD-1 antibodies as a targeted cancer therapy, which provides a rationale for therapeutic blockade of this axis in HPV-positive cancers.
Abstract: Background: Cervical cancer induced by infection with human papillomavirus (HPV) remains a leading cause of mortality for women worldwide although preventive vaccines and early diagnosis have reduced morbidity and mortality. Advanced cervical cancer can only be treated with either chemotherapy or radiotherapy but outcomes are poor. The median survival for advanced cervical cancer patients is only 16.8 months. Methods: We undertook a structural search of peer-reviewed published studies based on 1). Characteristics of programmed cell death ligand-1/programmed cell death-1(PD-L1/PD-1) expression in cervical cancer and upstream regulatory signals of PD-L1/PD-1 expression, 2). The role of the PD-L1/PD-1 axis in cervical carcinogenesis induced by HPV infection and 3). Whether the PD-L1/PD-1 axis has emerged as a potential target for cervical cancer therapies. Results: One hundred and twenty-six published papers were included in the review, demonstrating that expression of PD-L1/PD-1 is associated with HPV-caused cancer, especially with HPV 16 and 18 which account for approximately 70% of cervical cancer cases. HPV E5/E6/E7 oncogenes activate multiple signaling pathways including PI3K/AKT, MAPK, hypoxia-inducible factor 1α, STAT3/NF-kB and MicroRNAs, which regulate PD-L1/PD-1 axis to promote HPV-induced cervical carcinogenesis. The PD-L1/PD-1 axis plays a crucial role in immune escape of cervical cancer through inhibition of host immune response. creating an "immune-privileged" site for initial viral infection and subsequent adaptive immune resistance, which provides a rationale for therapeutic blockade of this axis in HPV-positive cancers. Currently, Phase I/II clinical trials evaluating the effects of PD-L1/PD-1 targeted therapies are in progress for cervical carcinoma, which provide an important opportunity for the application of anti-PD-L1/anti-PD-1 antibodies in cervical cancer treatment. Conclusion: Recent research developments have led to an entirely new class of drugs using antibodies against the PD-L1/PD-1 thus promoting the body’s immune system to fight the cancer. The expression and roles of the PD-L1/ PD-1 axis in the progression of cervical cancer provide great potential for using PD-L1/PD-1 antibodies as a targeted cancer therapy.

Journal ArticleDOI
TL;DR: This review critically summarizes the reports on the known and novel natural compounds including alkaloids, flavonoids, and saponins with a potent antidiabetic activity that were recently published from 2014 to 2019.
Abstract: Background Diabetes mellitus (DM) represents a global health problem characterized by hyperglycemia due to insufficient insulin secretion or failure of insulin activity. There is an imperative need for the discovery of alternative therapeutic agents that overcome the drawbacks of the current synthetic antidiabetic drugs. Objectives This review critically summarizes the reports on the known and novel natural compounds including alkaloids, flavonoids, and saponins with a potent antidiabetic activity that were recently published from 2014 to 2019. We discussed the underlying mechanisms of action that put these compounds in the category of effective antidiabetic candidates. Methods Information was obtained from Google Scholar, Scirus, PubMed, and Science Direct. Discussion and conclusion The reported natural compounds showed promising antidiabetic activity through different mechanisms such as the inhibition of α-amylase, α-glucosidase, insulin-sensitizing effect, direct action on protein tyrosine phosphatase 1B (PTP1B), peroxisome proliferator-activated receptors (PPARs), GLUT4 expression, insulin receptor substrate- 1 (IRS-1) and glycogen synthase kinase-3β (GSK-3β) as well as dipeptidyl peptidase-4 (DPP-4) enzyme. Some compounds inhibited the formation of advanced glycation end products (AGEs). Other compounds prevented the risk of diabetic complications such as cardiovascular diseases, retinopathy, and nephropathy. This review provides a critical overview of the most recent discoveries of antidiabetic agents from natural sources. This overview could help researchers to focus on the most prominent candidates aiming to develop new drug leads.

Journal ArticleDOI
TL;DR: In this paper, the toxicity of non-essential metals considering their peculiar chemical characteristics, such as different forms, hard-soft character, oxidation states, binding capabilities, and solubility, was discussed.
Abstract: BACKGROUND Essential metal ions play a specific and fundamental role in human metabolism. Their homeostasis is finely tuned, and any concentration imbalance in the form of deficiency or excess could lead to a progressive reduction and failure of normal biological function, to severe physiological and clinical outcomes, may eventually causing death. Conversely, non-essential metals are not necessary for life, and only noxious effects could arise after their exposure. Large environmental amounts of such chemicals come from both natural and anthropogenic sources, with the latter being predominant because of human activities. The dissipation of toxic metals contaminates water, air, soil, and food, causing a series of chronic and acute syndromes. OBJECTIVE This review discusses the toxicity of non-essential metals considering their peculiar chemical characteristics, such as different forms, hard-soft character, oxidation states, binding capabilities, and solubility, which can influence their speciation in biological systems, and subsequently, the main cellular targets. Particular focus is given to selected toxic metals, major non-essential metals, or semimetals related to toxicity, such as mercury, lead, cadmium, chromium, nickel, and arsenic. In addition, we provide indications on the possible treatments/interventions for metal poisoning based on chelation therapy. CONCLUSION Toxic metal ions can exert their peculiar harmful effects in several ways. They strongly coordinate with important biological molecules on the basis of their chemical- physical characteristics (mainly HSAB properties) or replace essential metal ions from their natural locations in proteins, enzymes, or hard structures, such as bones or teeth. Metals with redox properties could be key inducers of reactive oxygen species, leading to oxidative stress and cellular damage. Therapeutic detoxification, through complexation of toxic metal ions by specific chelating agents, appears an efficacious clinical strategy, mainly in acute cases of metal intoxication.

Journal ArticleDOI
TL;DR: The potential effects of curcumin on the phenotypes and functions of DCs as the key players in orchestration, stimulation, and modulation of the immune responses are summarized.
Abstract: Dendritic cells (DCs) are the most powerful antigen-presenting cells which link the innate and adaptive immune responses. Depending on the context, DCs initiate the immune responses or contribute to immune tolerance. Any disturbance in their phenotypes and functions may initiate inflammatory or autoimmune diseases. Hence, dysregulated DCs are the most attractive pharmacological target for the development of new therapies aiming at reducing their immunogenicity and at enhancing their tolerogenicity. Curcumin is the polyphenolic phytochemical component of the spice turmeric with a wide range of pharmacological activities. It acts in several ways as a modulator of DCs and converts them into tolerogenic DCs. Tolerogenic DCs possess anti-inflammatory and immunomodulatory activities that regulate the immune responses in health and disease. Curcumin by blocking maturation markers, cytokines and chemokines expression, and disrupting the antigen-presenting machinery of DCs render them non- or hypo-responsive to immunostimulants. It also reduces the expression of co-stimulatory and adhesion molecules on DCs and prevents them from both migration and antigen presentation but enhances their endocytosis capacity. Hence, curcumin causes DCs-inducing regulatory T cells and dampens CD4+ T helper 1 (Th1), Th2, and Th17 polarization. Inhibition of transcription factors such as NF-κB, AP-1, MAPKs (p38, JNK, ERK) and other intracellular signaling molecules such as JAK/STAT/SOCS provide a plausible explanation for most of these observations. In this review, we summarize the potential effects of curcumin on the phenotypes and functions of DCs as the key players in orchestration, stimulation, and modulation of the immune responses.

Journal ArticleDOI
Wen Xu1, Mengdan Ding1, Bei Wang1, Yuxuan Cai1, Chong Guo1, Chengfu Yuan1 
TL;DR: Zhang et al. as mentioned in this paper conducted a comprehensive and systematic search in PubMed to reveal the biological functions and specific mechanisms of lncRNA MALAT1 in gastric cancer.
Abstract: Many experimental shreds of evidence have shown that lncRNA MALAT1 is related to proliferation ability, invasion and migration ability, autophagy ability, and chemoresistance in gastric cancer. Moreover, MALAT1 is related to metastasis and patient prognosis in gastric cancer. This review aims to reveal the biological functions and specific mechanisms of MALAT1 in gastric cancer. Methods After a comprehensive and systematic search in PubMed, various molecular mechanisms of MALAT1 in mediating gastric carcinogenesis are collated and summarized. Results MALAT1-mediated gastric cancer is involved in a variety of molecular mechanisms. For example, MALAT1 can enhance the proliferation ability of gastric cancer cells by inhibiting the expressions of miR-122, miR-1297, miR-22-3p, miR-202, etc. MALAT1 enhances the metastasis and invasion of gastric cancer by participating in EMT process, PI3-Akt and other pathways. MALAT1 enhances the proliferation and invasion of gastric cancer by inhibiting the function of tumor suppressor gene PCDH10. MALAT1 can increase the autophagy ability of gastric cancer cells by inhibiting miR-183 and increasing the level of autophagy markers. MALAT1 enhances chemical resistance by inhibiting UPF1 and miR-30e levels. Conclusions MALAT1 is tightly linked to gastric carcinogenesis through various molecular mechanisms. Moreover, MALAT1 is also closely associated with chemoresistance and poor prognosis in gastric cancer patients, suggesting the possibility of its use as a clinical therapeutic target and a promising independent risk factor for predicting patient prognosis.

Journal ArticleDOI
TL;DR: The research progress of VEGFR-2 inhibitors is reviewed in this paper from the aspects of the drug development and chemical synthesis.
Abstract: Tumor growth inhibition can be achieved by inhibiting angiogenesis, which has been a field of great concern in recent years. Important targets to inhibit angiogenesis include vascular endothelial growth factor receptor (VEGFR) and its homologous tyrosine kinase receptor. Anti-angiogenic therapy based on inhibition of VEGFR-2 is an effective clinical treatment strategy. The research progress of VEGFR-2 inhibitors is reviewed in this paper from the aspects of drug development and chemical synthesis.

Journal ArticleDOI
TL;DR: A review of recent works describing the activity of NGF in mental and metabolic disorders related to stress found that NGF levels undergo important variations after exposure to stressful events.
Abstract: Stress is a constant threat for homeostasis and is represented by different extrinsic and intrinsic stimuli (stressors, Hans Selye's "noxious agents"), such as aggressive behavior, fear, diseases, physical activity, drugs, surgical injury, and environmental and physiological changes Our organisms respond to stress by activating the adaptive stress system to activate compensatory responses for restoring homeostasis Nerve Growth Factor (NGF) was discovered as a signaling molecule involved in survival, protection, differentiation, and proliferation of sympathetic and peripheral sensory neurons NGF mediates stress with an important role in translating environmental stimuli into physiological and pathological feedbacks since NGF levels undergo important variations after exposure to stressful events Psychological stress, lifestyle stress, and oxidative stress are well known to increase the risk of mental disorders such as schizophrenia, major depressive disorders, bipolar disorder, alcohol use disorders and metabolic disorders such as metabolic syndrome This review reports recent works describing the activity of NGF in mental and metabolic disorders related to stress