Simultaneous determination of tilianin and its metabolites in mice using ultra‐high‐performance liquid chromatography with tandem mass spectrometry and its application to a pharmacokinetic study

Tilianin is an active flavonoid glycoside found in many medical plants. Data are lacking regarding its pharmacokinetics and disposition in vivo. The objective of this study was to develop a sensitive, reliable and validated ultra‐high‐performance liquid chromatography with tandem mass spectrometry (UHPLC–MS/MS) method to simultaneously quantify tilianin and its main metabolites and to determine its pharmacokinetics in wild‐type and breast cancer resistance protein knockout (Bcrp1−/−) FVB mice. Chromatographic separation was accomplished on a C₁₈ column by utilizing acetonitrile and 0.5 mm ammonium acetate as the mobile phase. Mass spectrometric detection was performed using electrospray ionization in both positive and negative modes. The results showed that the precision, accuracy and recovery, as well as the stability of tilianin and its metabolites in mouse plasma, were all within acceptable limits. Acacetin‐7‐glucuronide and acacetin‐7‐sulfate were the major metabolites of tilianin in mouse plasma. Moreover, systemic exposure of acacetin‐7‐sulfate was significantly higher in Bcrp1 (−/−) FVB mice compared with wild‐type FVB mice. In conclusion, the fully validated UHPLC–MS/MS method was sensitive, reliable, and was successfully applied to assess the pharmacokinetics of tilianin in wild‐type and Bcrp1 (−/−) FVB mice. Breast cancer resistance protein had a significant impact on the elimination of the sulfated metabolite of tilianin in vivo.     

Chemistry,Biosynthesis and Pharmacology of Sarsasapogenin: A Potential Natural Steroid Molecule for New Drug Design,Development and Therapy

Sarsasapogenin is a natural steroidal sapogenin molecule obtained mainly from Anemarrhena asphodeloides Bunge. Among the various phytosteroids present, sarsasapogenin has emerged as a promising molecule due to the fact of its diverse pharmacological activities. In this review, the chemistry, biosynthesis and pharmacological potentials of sarsasapogenin are summarised. Between 1996 and the present, the relevant literature regarding sarsasapogenin was obtained from scientific databases including PubMed, ScienceDirect, Scopus, and Google Scholar. Overall, sarsasapogenin is a potent molecule with anti-inflammatory, anticancer, antidiabetic, anti-osteoclastogenic and neuroprotective activities. It is also a potential molecule in the treatment for precocious puberty. This review also discusses the metabolism, pharmacokinetics and possible structural modifications as well as obstacles and opportunities for sarsasapogenin to become a drug molecule in the near future. More comprehensive preclinical studies, clinical trials, drug delivery, formulations of effective doses in pharmacokinetics studies, evaluation of adverse effects and potential synergistic effects with other drugs need to be thoroughly investigated to make sarsasapogenin a potential molecule for future drug development.     

Snake Venom Components: Tools and Cures to Target Cardiovascular Diseases

Cardiovascular diseases (CVDs) are considered as a major cause of death worldwide. Therefore, identifying and developing therapeutic strategies to treat and reduce the prevalence of CVDs is a major medical challenge. Several drugs used for the treatment of CVDs, such as captopril, emerged from natural products, namely snake venoms. These venoms are complex mixtures of bioactive molecules, which, among other physiological networks, target the cardiovascular system, leading to them being considered in the development and design of new drugs. In this review, we describe some snake venom molecules targeting the cardiovascular system such as phospholipase A2 (PLA2), natriuretic peptides (NPs), bradykinin-potentiating peptides (BPPs), cysteine-rich secretory proteins (CRISPs), disintegrins, fibrinolytic enzymes, and three-finger toxins (3FTXs). In addition, their molecular targets, and mechanisms of action—vasorelaxation, inhibition of platelet aggregation, cardioprotective activities—are discussed. The dissection of their biological effects at the molecular scale give insights for the development of future snake venom-derived drugs.     

Tilianin alleviates airway inflammation in ovalbumin-induced allergic asthma in mice through the regulation of Th2 cytokines and TGF-β1/Smad markers

BackgroundAllergic asthma is a inflammatory disease defined as a condition of chronic airway inflammation. Asthma can be provoked by various stimuli like allergens inhalation like dust particles, pollen, and pollutants in the air.ObjectiveThis exploration was dedicated to investigate the anti-asthmatic properties of tilianin against the ovalbumin (OVA)-initiated asthma in mice.MethodologyThe asthma was provoked to the mice via administering 100 μl of aluminum hydroxide containing 20 μg of OVA and treated with the 10 and 20 mg/kg of tilianin, respectively. The levels of Th2 cytokines, OVA-specific IgE, eotaxin, pro-inflammatory mediators, antioxidants, and other markers were inspected by marker specific assay kits. The mRNA expressions of TGF-β1, Smad, iNOS, and COX-2 was assessed using RT-PCR analysis. The lung histology was analyzed microscopically to detect the histological changes.ResultsTilianin treatment remarkably suppressed the IL-4, IL-5, and IL-13, IFN-γ, eotaxin, and IgE levels. The NO, MPO, and inflammatory makers TNF-α, IL-6, IL-12, and TXB2 was substantially diminished by the tilianin treatment. The TGF-β1, iNOS, and COX-2 expressions were appreciably suppressed by the tilianin. The histological findings proved that the tilianin treatment alleviated the OVA-provoked histopathological changes in the lung tissues.ConclusionOur findings proved that tilianin effectively alleviated the OVA-provoked asthma in animals and it could be a talented anti-asthmatic candidate.     

Unravelling the Anticancer Mechanisms of Traditional Herbal Medicines with Metabolomics

Metabolite profiling of cancer cells presents many opportunities for anticancer drug discovery. The Chinese, Indian, and African flora, in particular, offers a diverse source of anticancer therapeutics as documented in traditional folklores. In-depth scientific information relating to mechanisms of action, quality control, and safety profile will promote their extensive usage in cancer therapy. Metabolomics may be a more holistic strategy to gain valuable insights into the anticancer mechanisms of action of plants but this has remained largely unexplored. This review, therefore, presents the available metabolomics studies on the anticancer effects of herbal medicines commonly used in Africa and Asia. In addition, we present some scientifically understudied ‘candidate plants’ for cancer metabolomics studies and highlight the relevance of metabolomics in addressing other challenges facing the drug development of anticancer herbs. Finally, we discussed the challenges of using metabolomics to uncover the underlying mechanisms of potential anticancer herbs and the progress made in this regard.     

Cyclin-Dependent Kinase 4 and 6 Inhibitors in Cell Cycle Dysregulation for Breast Cancer Treatment

In cell development, the cell cycle is crucial, and the cycle progression’s main controllers are endogenous CDK inhibitors, cyclin-dependent kinases (CDKs), and cyclins. In response to the mitogenic signal, cyclin D is produced and retinoblastoma protein (Rb) is phosphorylated due to activated CDK4/CDK6. This causes various proteins required in the cell cycle progression to be generated. In addition, complexes of CDK1-cyclin A/B, CDK2-cyclin E/A, and CDK4/CDK6-cyclin D are required in each phase of this progression. Cell cycle dysregulation has the ability to lead to cancer. Based on its role in the cell cycle, CDK has become a natural target of anticancer therapy. Therefore, understanding the CDK structures and the complex formed with the drug, helps to foster the development of CDK inhibitors. This development starts from non-selective CDK inhibitors to selective CDK4/CDK6 inhibitors, and these have been applied in clinical cancer treatment. However, these inhibitors currently require further development for various hematologic malignancies and solid tumors, based on the results demonstrated. In drug development, the main strategy is primarily to prevent and asphyxiate drug resistance, thus a determination of specific biomarkers is required to increase the therapy’s effectiveness as well as patient selection suitability in order to avoid therapy failure. This review is expected to serve as a reference for early and advanced-stage researchers in designing new molecules or repurposing existing molecules as CDK4/CDK6 inhibitors to treat breast cancer.     

Neuroprotective Potential of Chrysin: Mechanistic Insights and Therapeutic Potential for Neurological Disorders

Chrysin, a herbal bioactive molecule, exerts a plethora of pharmacological effects, including anti-oxidant, anti-inflammatory, neuroprotective, and anti-cancer. A growing body of evidence has highlighted the emerging role of chrysin in a variety of neurological disorders, including Alzheimer’s and Parkinson’s disease, epilepsy, multiple sclerosis, ischemic stroke, traumatic brain injury, and brain tumors. Based on the results of recent pre-clinical studies and evidence from studies in humans, this review is focused on the molecular mechanisms underlying the neuroprotective effects of chrysin in different neurological diseases. In addition, the potential challenges, and opportunities of chrysin’s inclusion in the neurotherapeutics repertoire are critically discussed.     

Genistein: A Potential Natural Lead Molecule for New Drug Design and Development for Treating Memory Impairment

Genistein is a naturally occurring polyphenolic molecule in the isoflavones group which is well known for its neuroprotection. In this review, we summarize the efficacy of genistein in attenuating the effects of memory impairment (MI) in animals. Scopus, PubMed, and Web of Science databases were used to find the relevant articles and discuss the effects of genistein in the brain, including its pharmacokinetics, bioavailability, behavioral effects, and some of the potential mechanisms of action on memory in several animal models. The results of the preclinical studies highly suggested that genistein is highly effective in enhancing the cognitive performance of the MI animal models, specifically in the memory domain, including spatial, recognition, retention, and reference memories, through its ability to reduce oxidative stress and attenuate neuroinflammation. This review also highlighted challenges and opportunities to improve the drug delivery of genistein for treating MI. Along with that, the possible structural modifications and derivatives of genistein to improve its physicochemical and drug-likeness properties are also discussed. The outcomes of the review proved that genistein can enhance the cognitive performance and ameliorate MI in different preclinical studies, thus indicating its potential as a natural lead for the design and development of a novel neuroprotective drug.     

Dietary Flavonoids: Cardioprotective Potential with Antioxidant Effects and Their Pharmacokinetic,Toxicological and Therapeutic Concerns

Flavonoids comprise a large group of structurally diverse polyphenolic compounds of plant origin and are abundantly found in human diet such as fruits, vegetables, grains, tea, dairy products, red wine, etc. Major classes of flavonoids include flavonols, flavones, flavanones, flavanols, anthocyanidins, isoflavones, and chalcones. Owing to their potential health benefits and medicinal significance, flavonoids are now considered as an indispensable component in a variety of medicinal, pharmaceutical, nutraceutical, and cosmetic preparations. Moreover, flavonoids play a significant role in preventing cardiovascular diseases (CVDs), which could be mainly due to their antioxidant, antiatherogenic, and antithrombotic effects. Epidemiological and in vitro/in vivo evidence of antioxidant effects supports the cardioprotective function of dietary flavonoids. Further, the inhibition of LDL oxidation and platelet aggregation following regular consumption of food containing flavonoids and moderate consumption of red wine might protect against atherosclerosis and thrombosis. One study suggests that daily intake of 100 mg of flavonoids through the diet may reduce the risk of developing morbidity and mortality due to coronary heart disease (CHD) by approximately 10%. This review summarizes dietary flavonoids with their sources and potential health implications in CVDs including various redox-active cardioprotective (molecular) mechanisms with antioxidant effects. Pharmacokinetic (oral bioavailability, drug metabolism), toxicological, and therapeutic aspects of dietary flavonoids are also addressed herein with future directions for the discovery and development of useful drug candidates/therapeutic molecules.     

Nanostructured Lipid Carriers-Hydrogels System for Drug Delivery: Nanohybrid Technology Perspective

Advanced hybrid component development in nanotechnology provides superior functionality in the application of scientific knowledge for the drug delivery industry. The purpose of this paper is to review important nanohybrid perspectives in drug delivery between nanostructured lipid carriers (NLC) and hydrogel systems. The hybrid system may result in the enhancement of each component’s synergistic properties in the mechanical strength of the hydrogel and concomitantly decrease aggregation of the NLC. The significant progress in nanostructured lipid carriers–hydrogels is reviewed here, with an emphasis on their preparation, potential applications, advantages, and underlying issues associated with these exciting materials.     

Ziziphus nummularia: A Comprehensive Review of Its Phytochemical Constituents and Pharmacological Properties

Ziziphus nummularia, a small bush of the Rhamnaceae family, has been widely used in traditional folk medicine, is rich in bioactive molecules, and has many reported pharmacological and therapeutic properties. Objective: To gather the current knowledge related to the medicinal characteristics of Z. nummularia. Specifically, its phytochemical contents and pharmacological activities in the treatment of various diseases such as cancer, diabetes, and cardiovascular diseases, are discussed. Methods: Major scientific literature databases, including PubMed, Scopus, ScienceDirect, SciFinder, Chemical Abstracts, Medicinal and Aromatic Plants Abstracts, Henriette’s Herbal Homepage, Dr. Duke’s Phytochemical and Ethnobotanical Databases, were searched to retrieve articles related to the review subject. General web searches using Google and Google scholar were also utilized. The search period covered articles published between 1980 and the end of October 2021.The search used the keywords ‘Ziziphus nummularia’, AND (‘phytochemical content’, ‘pharmacological properties, or activities, or effects, or roles’, ‘anti-inflammatory’, ‘anti-drought’, ‘anti-thermal’, ‘anthelmintic’, ‘antidiabetic’,’ anticancer’, ‘anticholinesterase’, ‘antimicrobial’, ‘sedative’, ‘antipyretic’, ‘analgesic’, or ‘gastrointestinal’). Results: This plant is rich in characteristic alkaloids, especially cyclopeptide alkaloids such as nummularine-M. Other phytochemicals, including flavonoids, saponins, glycosides, tannins, and phenolic compounds, are also present. These phytochemicals are responsible for the reported pharmacological properties of Z. nummularia, including anti-inflammatory, antioxidant, antimicrobial, anthelmintic, antidiabetic, anticancer, analgesic, and gastrointestinal activities. In addition, Z. nummularia has anti-drought and anti-thermal characteristics. Conclusion: Research into the phytochemical and pharmacological properties of Z. nummularia has demonstrated that this plant is a rich source of novel bioactive compounds. So far, Z. nummularia has shown a varied pharmacological profile (antioxidant, anticancer, anti-inflammatory, and cardioprotective), warranting further research to uncover the therapeutic potential of the bioactives of this plant. Taken together, Z. nummularia may represent a new potential target for the discovery of new drug leads.     

Recent Advances in Discovery of Lead Structures from Microbial Natural Products: Genomics- and Metabolomics-Guided Acceleration

Natural products (NPs) are evolutionarily optimized as drug-like molecules and remain the most consistently successful source of drugs and drug leads. They offer major opportunities for finding novel lead structures that are active against a broad spectrum of assay targets, particularly those from secondary metabolites of microbial origin. Due to traditional discovery approaches’ limitations relying on untargeted screening methods, there is a growing trend to employ unconventional secondary metabolomics techniques. Aided by the more in-depth understanding of different biosynthetic pathways and the technological advancement in analytical instrumentation, the development of new methodologies provides an alternative that can accelerate discoveries of new lead-structures of natural origin. This present mini-review briefly discusses selected examples regarding advancements in bioinformatics and genomics (focusing on genome mining and metagenomics approaches), as well as bioanalytics (mass-spectrometry) towards the microbial NPs-based drug discovery and development. The selected recent discoveries from 2015 to 2020 are featured herein.     

Changing need for bioanalysis during drug development

Recent years have witnessed the introduction of several high-quality review articles into the literature covering various scientific and technical aspects of bioanalysis, including chirality aspects. Now it is widely accepted that bioanalysis is an integral part of the pharmacokinetic/pharmacodynamic characterization of a novel chemical entity (NCE) from the time of its discovery and during various stages of drug development leading to its market authorization. There is a need for a comprehensive review article that takes into account the changing faces of bioanalysis from the time of inception of an NCE at the discovery stage and as the NCE moves forward in development. This review attempts to cover the versatility in the applicability of bioanalytical aspects with respect to the nature, rigor and available choices of analyses. For ease of understanding, bioanalytical aspects are discussed under sections covering discovery, preclinical and clinical stages. It is intended to give some general thoughts in this area which will form basis of a general framework as to how one would approach bioanalysis from inception (i.e. discovery of a lead molecule) and progressing through various stages of drug development.     

In Silico Molecular Docking and Simulation Studies of Protein HBx Involved in the Pathogenesis of Hepatitis B Virus-HBV

Current drug discovery involves finding leading drug candidates for further development. New scientific approaches include molecular docking, ADMET studies, and molecular dynamic simulation to determine targets and lead compounds. Hepatitis B is a disease of concern that is a life-threatening liver infection. The protein considered for the study was HBx. The hepatitis B X-interacting protein crystal structure was obtained from the PDB database (PDB ID-3MSH). Twenty ligands were chosen from the PubChem database for further in silico studies. The present study focused on in silico molecular docking studies using iGEMDOCK. The triethylene glycol monoethyl ether derivative showed an optimum binding affinity with the molecular target HBx, with a high negative affinity binding energy of −59.02 kcal/mol. Lipinski’s rule of five, Veber, and Ghose were followed in subsequent ADMET studies. Molecular dynamic simulation was performed to confirm the docking studies and to analyze the stability of the structure. In these respects, the triethylene glycol monoethyl ether derivative may be a promising molecule to prepare future hepatitis B drug candidates. Substantial research effort to find a promising drug for hepatitis B is warranted in the future.     

Antimicrobial Activity of Quercetin: An Approach to Its Mechanistic Principle

Quercetin, an essential plant flavonoid, possesses a variety of pharmacological activities. Extensive literature investigates its antimicrobial activity and possible mechanism of action. Quercetin has been shown to inhibit the growth of different Gram-positive and Gram-negative bacteria as well as fungi and viruses. The mechanism of its antimicrobial action includes cell membrane damage, change of membrane permeability, inhibition of synthesis of nucleic acids and proteins, reduction of expression of virulence factors, mitochondrial dysfunction, and preventing biofilm formation. Quercetin has also been shown to inhibit the growth of various drug-resistant microorganisms, thereby suggesting its use as a potent antimicrobial agent against drug-resistant strains. Furthermore, certain structural modifications of quercetin have sometimes been shown to enhance its antimicrobial activity compared to that of the parent molecule. In this review, we have summarized the antimicrobial activity of quercetin with a special focus on its mechanistic principle. Therefore, this review will provide further insights into the scientific understanding of quercetin’s mechanism of action, and the implications for its use as a clinically relevant antimicrobial agent.     

Tirzepatide,a New Era of Dual-Targeted Treatment for Diabetes and Obesity: A Mini-Review

The prevalence of obesity and diabetes is an increasing global problem, especially in developed countries, and is referred to as the twin epidemics. As such, advanced treatment approaches are needed. Tirzepatide, known as a ‘twincretin’, is a ‘first-in-class’ and the only dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) receptor agonist, that can significantly reduce glycemic levels and improve insulin sensitivity, as well as reducing body weight by more than 20% and improving lipid metabolism. This novel anti-diabetic drug is a synthetic peptide analog of the human GIP hormone with a C₂₀ fatty-diacid portion attached which, via acylation technology, can bind to albumin in order to provide a dose of the drug, by means of subcutaneous injection, once a week, which is appropriate to its a half-life of about five days. Tirzepatide, developed by Eli Lilly, was approved, under the brand name Mounjaro, by the United States Food and Drug Administration in May 2022. This started the ‘twincretin’ era of enormously important and appealing dual therapeutic options for diabetes and obesity, as well as advanced management of closely related cardiometabolic settings, which constitute the leading cause of morbidity, disability, and mortality worldwide. Herein, we present the key characteristics of tirzepatide in terms of synthesis, structure, and activity, bearing in mind its advantages and shortcomings. Furthermore, we briefly trace the evolution of this kind of medical agent and discuss the development of clinical studies.     

Anticancer,Cardio-Protective and Anti-Inflammatory Potential of Natural-Sources-Derived Phenolic Acids

Phenolic acids (PAs) are one of the utmost prevalent classes of plant-derived bioactive chemicals. They have a specific taste and odor, and are found in numerous medicinal and food plants, such as Cynomorium coccineum L., Prunus domestica (L.), and Vitis vinifera L. Their biosynthesis, physical and chemical characteristics and structure–activity relationship are well understood. These phytochemicals and their derivatives exert several bioactivities including but not limited to anticancer, cardioprotective, anti-inflammatory, immune-regulatory and anti-obesity properties. They are strong antioxidants because of hydroxyl groups which play pivotal role in their anticancer, anti-inflammatory and cardioprotective potential. They may play significant role in improving human health owing to anticarcinogenic, anti-arthritis, antihypertensive, anti-stroke, and anti-atherosclerosis activities, as several PAs have demonstrated biological activities against these disease during in vitro and in vivo studies. These PAs exhibited anticancer action by promoting apoptosis, targeting angiogenesis, and reducing abnormal cell growth, while anti-inflammatory activity was attributed to reducing proinflammatory cytokines. Pas exhibited anti-atherosclerotic activity via inhibition of platelets. Moreover, they also reduced cardiovascular complications such as myocardial infarction and stroke by activating Paraoxonase 1. The present review focuses on the plant sources, structure activity relationship, anticancer, anti-inflammatory and cardioprotective actions of PAs that is attributed to modulation of oxidative stress and signal transduction pathways, along with highlighting their mechanism of actions in disease conditions. Further, preclinical and clinical studies must be carried out to evaluate the mechanism of action and drug targets of PAs to understand their therapeutic actions and disease therapy in humans, respectively.     

Melatonin: A Neurotrophic Factor?

Melatonin, N-acetyl-5-hydroxytryptamine, is a hormone that synchronizes the internal environment with the photoperiod. It is synthesized in the pineal gland and greatly depends on the endogenous circadian clock located in the suprachiasmatic nucleus and the retina’s exposure to different light intensities. Among its most studied functions are the regulation of the waking-sleep rhythm and body temperature. Furthermore, melatonin has pleiotropic actions, which affect, for instance, the modulation of the immune and the cardiovascular systems, as well as the neuroprotection achieved by scavenging free radicals. Recent research has supported that melatonin contributes to neuronal survival, proliferation, and differentiation, such as dendritogenesis and axogenesis, and its processes are similar to those caused by Nerve Growth Factor, Brain-Derived Neurotrophic Factor, Neurotrophin-3, and Neurotrophin-4/5. Furthermore, this indolamine has apoptotic and anti-inflammatory actions in specific brain regions akin to those exerted by neurotrophic factors. This review presents evidence suggesting melatonin’s role as a neurotrophic factor, describes the signaling pathways involved in these processes, and, lastly, highlights the therapeutic implications involved.