Showing papers in "Frontiers in Pharmacology in 2019"

Drug Retention Rate and Predictive Factors of Drug Survival for Interleukin-1 Inhibitors in Systemic Juvenile Idiopathic Arthritis.

Abstract: Background and Objectives: Few studies have reported the drug retention rate (DRR) of biologic drugs in juvenile idiopathic arthritis (JIA), and none of them has specifically investigated the DRR of interleukin (IL)-1 inhibitors on systemic JIA (sJIA). This study aims to describe IL-1 inhibitors DRR and evaluate predictive factors of drug survival based on data from a real-world setting concerning sJIA. Methods: Medical records from sJIA patients treated with anakinra (ANA) and canakinumab (CAN) were retrospectively analyzed from 15 Italian tertiary referral centers. Results: Seventy seven patients were enrolled for a total of 86 treatment courses. The cumulative retention rate of the IL-1 inhibitors at 12-, 24-, 48-, and 60-months of follow-up was 79.9, 59.5, 53.5, and 53.5%, respectively, without any statistically significant differences between ANA and CAN (p = 0.056), and between patients treated in monotherapy compared to the subgroup co-administered with conventional immunosuppressors (p = 0.058). On the contrary, significant differences were found between biologic-naive patients and those previously treated with biologic drugs (p = 0.038) and when distinguishing according to adverse events (AEs) occurrence (p = 0.04). In regression analysis, patients pre-treated with other biologics (HR = 3.357 [CI: 1.341-8.406], p = 0.01) and those experiencing AEs (HR = 2.970 [CI: 1.186-7.435], p = 0.020) were associated with a higher hazard ratio of IL-1 inhibitors withdrawal. The mean treatment delay was significantly higher among patients discontinuing IL-1 inhibitors (p = 0.0002). Conclusions: Our findings suggest an excellent overall DRR for both ANA and CAN that might be further augmented by paying attention to AEs and employing these agents as first-line biologics in an early disease phase.

Network Pharmacology Databases for Traditional Chinese Medicine: Review and Assessment.

Abstract: The research field of systems biology has greatly advanced, and as a result, the concept of network pharmacology has been developed. This advancement, in turn, has shifted the paradigm from a “one-target, one-drug” mode to a “network-target, multiple-component-therapeutics” mode. Network pharmacology is more effective for establishing a “compound-protein/gene-disease” network and revealing the regulation principles of small molecules in a high-throughput manner. This approach makes it very powerful for the analysis of drug combinations, especially Traditional Chinese Medicine (TCM) preparations. In this work, we first summarized the databases and tools currently used for TCM research. Second, we focused on several representative applications of network pharmacology for TCM research, including studies on TCM compatibility, TCM target prediction, and TCM network toxicology research. Third, we compared the general statistics of several current TCM databases and evaluated and compared the search results of these databases based on 10 famous herbs. In summary, network pharmacology is a rational approach for TCM studies, and with the development of TCM research, powerful and comprehensive TCM databases have emerged but need further improvements. Additionally, given that several diseases could be treated by TCMs, with the mediation of gut microbiota, future studies should focus on both microbiome and TCMs to better understand and treat microbiome-related diseases.

Pathway Based Analysis of Mutation Data Is Efficient for Scoring Target Cancer Drugs.

Abstract: Despite the significant achievements in chemotherapy, cancer remains one of the leading causes of death. Target therapy revolutionized this field, but efficiencies of target drugs show dramatic variation among individual patients. Personalization of target therapies remains, therefore, a challenge in oncology. Here, we proposed molecular pathway-based algorithm for scoring of target drugs using high throughput mutation data to personalize their clinical efficacies. This algorithm was validated on 3,800 exome mutation profiles from The Cancer Genome Atlas (TCGA) project for 128 target drugs. The output values termed Mutational Drug Scores (MDS) showed positive correlation with the published drug efficiencies in clinical trials. We also used MDS approach to simulate all known protein coding genes as the putative drug targets. The model used was built on the basis of 18,273 mutation profiles from COSMIC database for eight cancer types. We found that the MDS algorithm-predicted hits frequently coincide with those already used as targets of the existing cancer drugs, but several novel candidates can be considered promising for further developments. Our results evidence that the MDS is applicable to ranking of anticancer drugs and can be applied for the identification of novel molecular targets.

Neuroinflammation as a Common Feature of Neurodegenerative Disorders.

Abstract: Neurodegenerative diseases share the fact that they derive from altered proteins that undergo an unfolding process followed by formation of β-structures and a pathological tendency to self-aggregate in neuronal cells. This is a characteristic of tau protein in Alzheimer's disease and several tauopathies associated with tau unfolding, α-synuclein in Parkinson's disease, and huntingtin in Huntington disease. Usually, the self-aggregation products are toxic to these cells, and toxicity spreads all over different brain areas. We have postulated that these protein unfolding events are the molecular alterations that trigger several neurodegenerative disorders. Most interestingly, these events occur as a result of neuroinflammatory cascades involving alterations in the cross-talks between glial cells and neurons as a consequence of the activation of microglia and astrocytes. The model we have hypothesized for Alzheimer's disease involves damage signals that promote glial activation, followed by nuclear factor NF-kβ activation, synthesis, and release of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, and IL-12 that affect neuronal receptors with an overactivation of protein kinases. These patterns of pathological events can be applied to several neurodegenerative disorders. In this context, the involvement of innate immunity seems to be a major paradigm in the pathogenesis of these diseases. This is an important element for the search for potential therapeutic approaches for all these brain disorders.

Carbon-Based Nanomaterials for Biomedical Applications: A Recent Study.

Abstract: The study of carbon-based nanomaterials (CBNs) for biomedical applications has attracted great attention due to their unique chemical and physical properties including thermal, mechanical, electrical, optical and structural diversity. With the help of these intrinsic properties, CBNs, including carbon nanotubes (CNT), graphene oxide (GO), and graphene quantum dots (GQDs), have been extensively investigated in biomedical applications. This review summarizes the most recent studies in developing of CBNs for various biomedical applications including bio-sensing, drug delivery and cancer therapy.

GPCR Signaling Regulation: The Role of GRKs and Arrestins

Abstract: Every animal species expresses hundreds of different G protein-coupled receptors (GPCRs) that respond to a wide variety of external stimuli. GPCRs-driven signaling pathways are involved in pretty much every physiological function and in many pathologies. Therefore, GPCRs are targeted by about a third of clinically used drugs. The signaling of most GPCRs via G proteins is terminated by the phosphorylation of active receptor by specific kinases (GPCR kinases, or GRKs) and subsequent binding of arrestin proteins, that selectively recognize active phosphorylated receptors. In addition, GRKs and arrestins play a role in multiple signaling pathways in the cell, both GPCR-initiated and receptor-independent. Here we focus on the mechanisms of GRK- and arrestin-mediated regulation of GPCR signaling, which includes homologous desensitization and redirection of signaling to additional pathways by bound arrestins.

Nanoparticles in the Treatment of Infections Caused by Multidrug-Resistant Organisms

Abstract: Nanotechnology using nanoscale materials is increasingly being utilized for clinical applications, especially as a new paradigm for infectious diseases. Infections caused by multidrug-resistant organisms (MDROs) are emerging as causes of morbidity and mortality worldwide. Antibiotic options for infections caused by MDROs are often limited. These clinical challenges highlight the critical demand for alternative and effective antimicrobial strategies. Nanoparticles (NPs) can penetrate the cell membrane of pathogenic microorganisms and interfere with important molecular pathways, formulating unique antimicrobial mechanisms. In combination with optimal antibiotics, NPs have demonstrated synergy and may aid in limiting the global crisis of emerging bacterial resistance. In this review, we summarized current research on the broad classification of the NPs that have shown in vitro antimicrobial activity against MDROs, including the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). The pharmacokinetics and pharmacodynamic characteristics of NPs and bacteria-resistant mechanisms to NPs were also discussed.

Advantages and Limitations of Bacteriophages for the Treatment of Bacterial Infections.

Abstract: Bacteriophages (BPs) are viruses that can infect and kill bacteria without any negative effect on human or animal cells. For this reason, it is supposed that they can be used, alone or in combination with antibiotics, to treat bacterial infections. In this narrative review, the advantages and limitations of BPs for use in humans will be discussed. PubMed was used to search for all of the studies published from January 2008 to December 2018 using the key words: "BPs" or "phages" and "bacterial infection" or "antibiotic" or "infectious diseases." More than 100 articles were found, but only those published in English or providing evidence-based data were included in the evaluation. Literature review showed that the rapid rise of multi-drug-resistant bacteria worldwide coupled with a decline in the development and production of novel antibacterial agents have led scientists to consider BPs for treatment of bacterial infection. Use of BPs to overcome the problem of increasing bacterial resistance to antibiotics is attractive, and some research data seem to indicate that it might be a rational measure. However, present knowledge seems insufficient to allow the use of BPs for this purpose. To date, the problem of how to prepare the formulations for clinical use and how to avoid or limit the risk of emergence of bacterial resistance through the transmission of genetic material are not completely solved problems. Further studies specifically devoted to solve these problems are needed before BPs can be used in humans.

Molecular Mechanisms of Action of Genistein in Cancer: Recent Advances

Abstract: Background: Genistein is one among the several other known isoflavones that is found in different soybeans and soy products. The chemical name of genistein is 4',5,7-trihydroxyisoflavone. Genistein has drawn attention of scientific community because of its potential beneficial effects on human grave diseases, such as cancer. Mechanistic insight of genistein reveals its potential for apoptotic induction, cell cycle arrest, as well as antiangiogenic, antimetastatic, and anti-inflammatory effects. Objective: The purpose of this review is to unravel and analyze various molecular mechanisms of genistein in diverse cancer models. Data sources: English language literature was searched using various databases, such as PubMed, ScienceDirect, EBOSCOhost, Scopus, Web of Science, and Cochrane Library. Key words used in various combinations included genistein, cancer, anticancer, molecular mechanisms prevention, treatment, in vivo, in vitro, and clinical studies. Study selection: Study selection was carried out strictly in accordance with the statement of Preferred Reporting Items for Systematic Reviews and Meta-analyses. Data extraction: Four authors independently carried out the extraction of articles. Data synthesis: One hundred one papers were found suitable for use in this review. Conclusion: This review covers various molecular interactions of genistein with various cellular targets in cancer models. It will help the scientific community understand genistein and cancer biology and will provoke them to design novel therapeutic strategies.

Gut Microbiota-Dependent Marker TMAO in Promoting Cardiovascular Disease: Inflammation Mechanism, Clinical Prognostic, and Potential as a Therapeutic Target.

Abstract: Cardiovascular disease (CVD) is the leading cause of death worldwide, especially in developed countries, and atherosclerosis (AS) is the common pathological basis of many cardiovascular diseases (CVDs) such as coronary heart disease (CHD). The role of the gut microbiota in AS has begun to be appreciated in recent years. Trimethylamine N-oxide (TMAO), an important gut microbe-dependent metabolite, is generated from dietary choline, betaine, and L-carnitine. Multiple studies have suggested a correlation between plasma TMAO levels and the risk of AS. However, the mechanism underlying this relationship is still unclear. In this review, we discuss the TMAO-involved mechanisms of atherosclerotic CVD from the perspective of inflammation, inflammation-related immunity, cholesterol metabolism, and atherothrombosis. We also summarize available clinical studies on the role of TMAO in predicting prognostic outcomes, including major adverse cardiovascular events (MACE), in patients presenting with AS. Finally, since TMAO may be a novel therapeutic target for AS, several therapeutic strategies including drugs, dietary, etc. to lower TMAO levels that are currently being explored are also discussed.

Inflammation in Renal Diseases: New and Old Players.

Abstract: Inflammation, a process intimately linked to renal disease, can be defined as a complex network of interactions between renal parenchymal cells and resident immune cells, such as macrophages and dendritic cells, coupled with recruitment of circulating monocytes, lymphocytes, and neutrophils. Once stimulated, these cells activate specialized structures such as Toll-like receptor and Nod-like receptor (NLR). By detecting danger-associated molecules, these receptors can set in motion major innate immunity pathways such as nuclear factor ĸB (NF-ĸB) and NLRP3 inflammasome, causing metabolic reprogramming and phenotype changes of immune and parenchymal cells and triggering the secretion of a number of inflammatory mediators that can cause irreversible tissue damage and functional loss. Growing evidence suggests that this response can be deeply impacted by the crosstalk between the kidneys and other organs, such as the gut. Changes in the composition and/or metabolite production of the gut microbiota can influence inflammation, oxidative stress, and fibrosis, thus offering opportunities to positively manipulate the composition and/or functionality of gut microbiota and, consequentially, ameliorate deleterious consequences of renal diseases. In this review, we summarize the most recent evidence that renal inflammation can be ameliorated by interfering with the gut microbiota through the administration of probiotics, prebiotics, and postbiotics. In addition to these innovative approaches, we address the recent discovery of new targets for drugs long in use in clinical practice. Angiotensin II receptor antagonists, NF-ĸB inhibitors, thiazide diuretics, and antimetabolic drugs can reduce renal macrophage infiltration and slow down the progression of renal disease by mechanisms independent of those usually attributed to these compounds. Allopurinol, an inhibitor of uric acid production, has been shown to decrease renal inflammation by limiting activation of the NLRP3 inflammasome. So far, these protective effects have been shown in experimental studies only. Clinical studies will establish whether these novel strategies can be incorporated into the arsenal of treatments intended to prevent the progression of human disease.

Astrocytes: Role and Functions in Brain Pathologies

Abstract: Astrocytes are a population of cells with distinctive morphological and functional characteristics that differ within specific areas of the brain. Postnatally, astrocyte progenitors migrate to reach their brain area and related properties. They have a regulatory role of brain functions that are implicated in neurogenesis and synaptogenesis, controlling blood-brain barrier permeability and maintaining extracellular homeostasis. Mature astrocytes also express some genes enriched in cell progenitors, suggesting they can retain proliferative potential. Considering heterogeneity of cell population, it is not surprising that their disorders are related to a wide range of different neuro-pathologies. Brain diseases are characterized by the active inflammatory state of the astrocytes, which is usually described as up-regulation of glial fibrillary acidic protein (GFAP). In particular, the loss of astrocytes function as a result of cellular senescence could have implications for the neurodegenerative disorders, such as Alzheimer disease and Huntington disease, and for the aging brain. Astrocytes can also drive the induction and the progression of the inflammatory state due to their Ca2+ signals and that it is strongly related to the disease severity/state. Moreover, they contribute to the altered neuronal activity in several frontal cortex pathologies such as ischemic stroke and epilepsy. There, we describe the current knowledge pertaining to astrocytes' role in brain pathologies and discuss the possibilities to target them as approach toward pharmacological therapies for neuro-pathologies.

Curcumin Nanoformulations for Colorectal Cancer: A Review

Abstract: Colorectal cancer (CRC) is the third most prevalent form of cancer, after lung cancer and breast cancer, with the second highest death incidence. Over the years, natural compounds have been explored as an alternative to conventional cancer therapies such as surgery, radiotherapy, and chemotherapy. Curcumin, an active constituent of turmeric has been associated with various health benefits. It has gained much attention as an anticancer agent due to its ability to regulate multiple cell signaling pathways, including NF-κB, STAT3, activated protein-1 (AP-1), epidermal growth response-1 (Egr-1), and p53, which are crucial in cancer development and progression. Nevertheless, the clinical application of curcumin is greatly restricted because of its low water solubility, poor oral absorption, and rapid metabolism. These issues have led to the development of curcumin nanoformulations to overcome the limitations of the compound. Nanotechnology-based delivery systems have been widely used in improving the delivery of poorly-water soluble drugs. Besides, these systems also come with the added benefits of possible cellular targeting and improvement in cellular uptake. An ideal improved formulation should display a greater anticancer activity compared to free curcumin, and at the same time be non-toxic to the normal cells. In this review, we focus on the design and development of various nanoformulations to deliver curcumin for use in CRC such as liposomes, micelles, polymer nanoparticles, nanogels, cyclodextrin complexes, solid lipid nanoparticles (SLN), phytosomes, and gold nanoparticles. We also discuss the current pre-clinical and clinical evidences of curcumin nanoformulations in CRC therapy, analyse the research gap, and address the future direction of this research area.

The Role of Nrf2 in Liver Disease: Novel Molecular Mechanisms and Therapeutic Approaches.

Abstract: Oxidative stress and inflammation are the most important pathogenic events in the development and progression of liver diseases. Nuclear erythroid 2-related factor 2 (Nrf2) is the master regulator of the cellular protection via induction of anti-inflammatory, antioxidant, and cyto-protective genes expression. Multiple studies have shown that activation or suppression of this transcriptional factor significantly affect progression of liver diseases. Comprehensive understanding the roles of Nrf2 activation/expression and the outcomes of its activators/inhibitors are indispensable for defining the mechanisms and therapeutic strategies against liver diseases. In this current review, we discussed recent advances in the function and principal mechanisms by regulating Nrf2 in liver diseases, including acute liver failure, hepatic ischemia-reperfusion injury (IRI), alcoholic liver disease (ALD), viral hepatitis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma (HCC).

The NCATS BioPlanet - An Integrated Platform for Exploring the Universe of Cellular Signaling Pathways for Toxicology, Systems Biology, and Chemical Genomics.

Abstract: Chemical genomics aims to comprehensively define, and ultimately predict, the effects of small molecule compounds on biological systems. Chemical activity profiling approaches must consider chemical effects on all pathways operative in mammalian cells. To enable a strategic and maximally efficient chemical profiling of pathway space, we have created the NCATS BioPlanet, a comprehensive integrated pathway resource that incorporates the universe of 1,658 human pathways sourced from publicly available, manually curated sources, which have been subjected to thorough redundancy and consistency cross-evaluation. BioPlanet supports interactive browsing, retrieval, and analysis of pathways, exploration of pathway connections, and pathway search by gene targets, category, and availability of corresponding bioactivity assay, as well as visualization of pathways on a 3-dimensional globe, in which the distance between any two pathways is proportional to their degree of gene component overlap. Using this resource, we propose a strategy to identify a minimal set of 362 biological assays that can interrogate the universe of human pathways. The NCATS BioPlanet is a public resource, which will be continually expanded and updated, for systems biology, toxicology, and chemical genomics, available at http://tripod.nih.gov/bioplanet/.

Mitochondria as Potential Targets in Alzheimer Disease Therapy: An Update.

Abstract: Alzheimer disease (AD) is a progressive and deleterious neurodegenerative disorder that affects mostly the elderly population. At the moment, no effective treatments are available in the market, making the whole situation a compelling challenge for societies worldwide. Recently, novel mechanisms have been proposed to explain the etiology of this disease leading to the new concept that AD is a multifactor pathology. Among others, the function of mitochondria has been considered as one of the intracellular processes severely compromised in AD since the early stages and likely represents a common feature of many neurodegenerative diseases. Many mitochondrial parameters decline already during the aging, reaching an extensive functional failure concomitant with the onset of neurodegenerative conditions, although the exact timeline of these events is still unclear. Thereby, it is not surprising that mitochondria have been already considered as therapeutic targets in neurodegenerative diseases including AD. Together with an overview of the role of mitochondrial dysfunction, this review examines the pros and cons of the tested therapeutic approaches targeting mitochondria in the context of AD. Since mitochondrial therapies in AD have shown different degrees of progress, it is imperative to perform a detailed analysis of the significance of mitochondrial deterioration in AD and of a pharmacological treatment at this level. This step would be very important for the field, as an effective drug treatment in AD is still missing and new therapeutic concepts are urgently needed.

Environmental Stressors on Skin Aging. Mechanistic Insights.

Abstract: The skin is the main barrier that protects us against environmental stressors (physical, chemical, and biological). These stressors, combined with internal factors, are responsible for cutaneous aging. Furthermore, they negatively affect the skin and increase the risk of cutaneous diseases, particularly skin cancer. This review addresses the impact of environmental stressors on skin aging, especially those related to general and specific external factors (lifestyle, occupation, pollutants, and light exposure). More specifically, we have evaluated ambient air pollution, household air pollutants from non-combustion sources, and exposure to light (ultraviolet radiation and blue and red light). We approach the molecular pathways involved in skin aging and pathology as a result of exposure to these external environmental stressors. Finally, we reflect on how components of environmental stress can interact with ultraviolet radiation to cause cell damage and the critical importance of knowing the mechanisms to develop new therapies to maintain the skin without damage in old age and to repair its diseases.

Formononetin: A Review of Its Anticancer Potentials and Mechanisms

Abstract: Cancer, a complex yet common disease, is caused by uncontrolled cell division and abnormal cell growth due to a variety of gene mutations. Seeking effective treatments for cancer is a major research focus, as the incidence of cancer is on the rise and drug resistance to existing anti-cancer drugs is major concern. Natural products have the potential to yield unique molecules and combinations of substances that may be effective against cancer with relatively low toxicity/better side effect profile compared to standard anticancer therapy. Drug discovery work with natural products has demonstrated that natural compounds display a wide range of biological activities correlating to anticancer effects. In this review, we discuss formononetin (C16H12O4), which originates mainly from red clovers and the Chinese herb Astragalus membranaceus. The compound comes from a class of 7-hydroisoflavones with a substitution of methoxy group at position 4. Formononetin elicits antitumorigenic properties in vitro and in vivo by modulating numerous signaling pathways to induce cell apoptosis (by intrinsic pathway involving Bax, Bcl-2, and caspase-3 proteins) and cell cycle arrest (by regulating mediators like cyclin A, cyclin B1, and cyclin D1), suppress cell proliferation [by signal transducer and activator of transcription (STAT) activation, phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT), and mitogen-activated protein kinase (MAPK) signaling pathway], and inhibit cell invasion [by regulating growth factors vascular endothelial growth factor (VEGF) and Fibroblast growth factor 2 (FGF2), and matrix metalloproteinase (MMP)-2 and MMP-9 proteins]. Co-treatment with other chemotherapy drugs such as bortezomib, LY2940002, U0126, sunitinib, epirubicin, doxorubicin, temozolomide, and metformin enhances the anticancer potential of both formononetin and the respective drugs through synergistic effect. Compiling the evidence thus far highlights the potential of formononetin to be a promising candidate for chemoprevention and chemotherapy.

Salvia miltiorrhiza in Treating Cardiovascular Diseases: A Review on Its Pharmacological and Clinical Applications.

Abstract: Bioactive chemical constitutes from the root of Salvia miltiorrhiza classified in two major groups, viz., liposoluble tanshinones and water-soluble phenolics. Tanshinone IIA is a major lipid-soluble compound having promising health benefits. The in vivo and in vitro studies showed that the tanshinone IIA and salvianolate have a wide range of cardiovascular and other pharmacological effects, including antioxidative, anti-inflammatory, endothelial protective, myocardial protective, anticoagulation, vasodilation, and anti-atherosclerosis, as well as significantly help to reduce proliferation and migration of vascular smooth muscle cells. In addition, some of the clinical studies reported that the S. miltiorrhiza preparations in combination with Western medicine were more effective for treatment of various cardiovascular diseases including angina pectoris, myocardial infarction, hypertension, hyperlipidemia, and pulmonary heart diseases. In this review, we demonstrated the potential applications of S. miltiorrhiza, including pharmacological effects of salvianolate, tanshinone IIA, and its water-soluble derivative, like sodium tanshinone IIA sulfonate. Moreover, we also provided details about the clinical applications of S. miltiorrhiza preparations in controlling the cardiovascular diseases.

In silico ADME and Toxicity Prediction of Ceftazidime and Its Impurities

Abstract: To improve the quality control of drugs, we predicted the absorption, distribution, metabolism, excretion, and toxicity (ADMET) of ceftazidime (CAZ) and its impurities via in silico methods. We used three types of quantitative structure-activity relationship and docking software for precise prediction: Discovery Studio 4.0, OECD QSAR Toolbox 4.1, Toxtree, and the pkCSM approach. The pharmacokinetics and toxicity of ceftazidime and impurity A (Δ-2-CAZ) are similar. The biological properties of impurity B (CAZ E-isomer) are different from CAZ. Therefore, we focused on drug stability to analyze impurity B. Impurities D and I have strong lipophilicity, good intestinal absorption, and poor excretion in the body. Impurity D is particularly neurotoxic and genotoxic. It is important to control the content of impurity D. The toxicity of impurity F is low, but the toxicity is enhanced when it becomes the C-3 side chain of CAZ and forms a quaternary amine group. We conclude that the beta-lactam ring of nucleus, the quaternary amine group at the C-3 side chain, and the acetates at the C-7 side chain of CAZ are the main toxic functional groups. Impurities B and D may be the genetic impurity in CAZ and may also have neurotoxicity. This in silico approach can predict the toxicity of other cephalosporins and impurities.

Integrating Network Pharmacology and Pharmacological Evaluation for Deciphering the Action Mechanism of Herbal Formula Zuojin Pill in Suppressing Hepatocellular Carcinoma.

Abstract: Hepatocellular carcinoma (HCC) is a kind of complicated disease with an increasing incidence all over the world. A classic Chinese medicine formula, Zuojin pill (ZJP), was shown to exert therapeutic effects on HCC. However, its chemical and pharmacological profiles remain to be elucidated. In the current study, network pharmacology approach was applied to characterize the action mechanism of ZJP on HCC. All compounds were obtained from the corresponding databases, and active compounds were selected according to their oral bioavailability and drug-likeness index. The potential proteins of ZJP were obtained from the traditional Chinese medicine systems pharmacology (TCMSP) database and the traditional Chinese medicine integrated database (TCMID), whereas the potential genes of HCC were obtained from OncoDB.HCC and Liverome databases. The potential pathways related to genes were determined by gene ontology (GO) and pathway enrichment analyses. The compound-target and target-pathway networks were constructed. Subsequently, the potential underlying action mechanisms of ZJP on HCC predicted by the network pharmacology analyses were experimentally validated in HCC cellular and orthotopic HCC implantation murine models. A total of 224 components in ZJP were obtained, among which, 42 were chosen as bioactive components. The compound-target network included 32 compounds and 86 targets, whereas the target-pathway network included 70 proteins and 75 pathways. The in vitro and in vivo experiments validated that ZJP exhibited its prominent therapeutic effects on HCC mainly via the regulation of cell proliferation and survival though the EGFR/MAPK, PI3K/NF-κB, and CCND1 signaling pathways. In conclusion, our study suggested combination of network pharmacology prediction with experimental validation may offer a useful tool to characterize the molecular mechanism of traditional Chinese medicine (TCM) ZJP on HCC.

Recent Trends of the Bio-Inspired Nanoparticles in Cancer Theranostics.

Abstract: In recent years, various nanomaterials have emerged as an exciting tool in cancer theranostic applications due to their multifunctional property and intrinsic molecular property aiding effective diagnosis, imaging, and successful therapy. However, chemically synthesized nanoparticles have several issues related to the cost, toxicity and effectiveness. In this context, bio-inspired nanoparticles (NPs) held edges over conventionally synthesized nanoparticles due to their low cost, easy synthesis and low toxicity. In this present review article, a detailed overview of the cancer theranostics applications of various bio-inspired has been provided. This includes the recent examples of liposomes, lipid nanoparticles, protein nanoparticles, inorganic nanoparticles, and viral nanoparticles. Finally, challenges and the future scopes of these NPs in cancer therapy and diagnostics applications are highlighted.

Current Development of siRNA Bioconjugates: From Research to the Clinic.

Abstract: Small interfering RNAs (siRNAs) acting via RNA interference mechanisms are able to recognize a homologous mRNA sequence in the cell and induce its degradation. The main problems in the development of siRNA-based drugs for therapeutic use are the low efficiency of siRNA delivery to target cells and the degradation of siRNAs by nucleases in biological fluids. Various approaches have been proposed to solve the problem of siRNA delivery in vivo (e.g., viruses, cationic lipids, polymers, nanoparticles), but all have limitations for therapeutic use. One of the most promising approaches to solve the problem of siRNA delivery to target cells is bioconjugation; i.e., the covalent connection of siRNAs with biogenic molecules (lipophilic molecules, antibodies, aptamers, ligands, peptides, or polymers). Bioconjugates are “ideal nanoparticles” since they do not need a positive charge to form complexes, are less toxic, and are less effectively recognized by components of the immune system because of their small size. This review is focused on strategies and principles for constructing siRNA bioconjugates for in vivo use.

Macrophage Death as a Pharmacological Target in Atherosclerosis.

Abstract: Atherosclerosis is a chronic inflammatory disorder characterized by the gradual build-up of plaques within the vessel wall of middle-sized and large arteries Over the past decades, treatment of atherosclerosis mainly focused on lowering lipid levels, which can be accomplished by the use of statins However, some patients do not respond sufficiently to statin therapy and therefore still have a residual cardiovascular risk This issue highlights the need for novel therapeutic strategies As macrophages are implicated in all stages of atherosclerotic lesion development, they represent an important alternative drug target A variety of anti-inflammatory strategies have recently emerged to treat or prevent atherosclerosis Here, we review the canonical mechanisms of macrophage death and their impact on atherogenesis and plaque stability Macrophage death is a prominent feature of advanced plaques and is a major contributor to necrotic core formation and plaque destabilization Mechanisms of macrophage death in atherosclerosis include apoptosis, passive or accidental necrosis as well as secondary necrosis, a type of death that typically occurs when apoptotic cells are insufficiently cleared by neighboring cells via a phagocytic process termed efferocytosis In addition, less-well characterized types of regulated necrosis in macrophages such as necroptosis, pyroptosis, ferroptosis, and parthanatos may occur in advanced plaques and are also discussed Autophagy in plaque macrophages is an important survival pathway that protects against cell death, yet massive stimulation of autophagy promotes another type of death, usually referred to as autosis Multiple lines of evidence indicate that a better insight into the different mechanisms of macrophage death, and how they mutually interact, will provide novel pharmacological strategies to resolve atherosclerosis and stabilize vulnerable, rupture-prone plaques

The Signaling Pathways, and Therapeutic Targets of Antiviral Agents: Focusing on the Antiviral Approaches and Clinical Perspectives of Anthocyanins in the Management of Viral Diseases.

Abstract: As the leading cause of death worldwide, viruses significantly affect global health. Despite the rapid progress in human healthcare, there are few viricidal and antiviral therapies that are efficient enough. The rapid emergence of resistance, and high costs, as well as the related side effects of synthetic antiviral drugs, raise the need to identify novel, effective, and safe alternatives against viral diseases. Nature has been of the most exceptional help and source of inspiration for developing novel multi-target antiviral compounds, affecting several steps of the viral life cycle and host proteins. For that matter and due to safety and efficacy limitations, as well as high resistance rate of conventional therapies, hundreds of natural molecules are preferred over the synthetic drugs. Besides, natural antiviral agents have shown acceptable antiviral value in both preclinical and clinical trials.This is the first review regarding molecular and cellular pathways of the virus life cycle, treatment strategies, and therapeutic targets of several viral diseases with a particular focus on anthocyanins as promising natural compounds for significant antiviral enhancements. Clinical applications and the need to develop nano-formulation of anthocyanins in drug delivery systems are also considered.

Flavonoids as Natural Anti-Inflammatory Agents Targeting Nuclear Factor-Kappa B (NFκB) Signaling in Cardiovascular Diseases: A Mini Review.

Abstract: Cardiovascular diseases (CVDs) such as angina, hypertension, myocardial ischemia, and heart failure are the leading causes of morbidity and mortality worldwide. One of the major transcription factors widely associated with CVDs is nuclear factor-kappa B (NFκB). NFκB activation initiates the canonical and non-conical pathways that promotes activation of transcription factors leading to inflammation, such as leukocyte adhesion molecules, cytokines, and chemokines. Flavonoids are bioactive polyphenolic compounds found abundantly in various fruits, vegetables, beverages (tea, coffee), nuts, and cereal products with cardiovascular protective properties. Flavonoids can be classified into six subgroups based on their chemical structures: flavanones, flavones, flavonols, flavan-3-ols, isoflavones, and anthocyanidins. As NFκB inhibitors, these flavonoids may modulate the expression of pro-inflammatory genes leading to the attenuation of the inflammatory responses underlying various cardiovascular pathology. This review presents an update on the anti-inflammatory actions of flavonoids via inhibition of NFκB mechanism supporting the therapeutic potential of these natural compounds in various CVDs.

Systems Pharmacology for Investigation of the Mechanisms of Action of Traditional Chinese Medicine in Drug Discovery.

Abstract: As a traditional medical intervention in Asia and a complementary and alternative medicine in western countries, traditional Chinese medicine (TCM) has attracted global attention in the life science field. TCM provides extensive natural resources for medicinal compounds, and these resources are generally regarded as effective and safe for use in drug discovery. However, owing to the complexity of compounds and their related multiple targets of TCM, it remains difficult to dissect the mechanisms of action of herbal medicines at a holistic level. To solve the issue, in the review, we proposed a novel approach of systems pharmacology to identify the bioactive compounds, predict their related targets, and illustrate the molecular mechanisms of action of TCM. With a predominant focus on the mechanisms of actions of TCM, we also highlighted the application of the systems pharmacology approach for the prediction of drug combination and dynamic analysis, the synergistic effects of TCMs, formula dissection, and theory analysis. In summary, the systems pharmacology method contributes to understand the complex interactions among biological systems, drugs, and complex diseases from a network perspective. Consequently, systems pharmacology provides a novel approach to promote drug discovery in a precise manner and a systems level, thus facilitating the modernization of TCM.

Sustained Delivery System for Stem Cell-Derived Exosomes

Abstract: Recent literature has ascribed that the paracrine action of stem cells is mediated by exosomes. Exosomes are nano-sized extracellular vesicles (30 to 100 nm) of endocytic origin that play important roles in intercellular communication. They have the ability to deliver various therapeutic effects, e.g., skin regeneration or cardiac function recovery, when applied topically or injected systemically. However, injection of exosomes has been shown to result in rapid clearance from blood circulation and accumulation of the exosomes in the liver, spleen, lung, and gastrointestinal tract can be found as early as 2 h after injection. Topical administration of exosomes on the skin or ocular surface would suffer the same fate due to rapid fluid turnover (sweat or tears). Biodegradable or highly porous hydrogels have been utilized to load exosomes and to deliver a sustained therapeutic effect. They can also prevent the exosomes from being cleared prematurely and allow the delivery of a more localized and concentrated exosome dosage by placing the hydrogel directly at or in the proximity of the target site. In this mini-review, we elaborate on the challenges of conventional exosome administration and highlight the solution to the shortcomings in the form of exosome-incorporated hydrogels. Different techniques to encapsulate exosomes and examples of hydrogels that have been used to create sustained delivery systems of exosomes are also discussed.

Natural Plants Compounds as Modulators of Epithelial-to-Mesenchymal Transition.

Abstract: Epithelial-to-mesenchymal transition (EMT) is a self-regulated physiological process required for tissue repair that, in non-controled conditions may lead to fibrosis, angiogenesis, loss of normal organ function or cancer. Although several molecular pathways involved in EMT regulation have been described, this process does not have any specific treatment. This article introduces a systematic review of effective natural plant compounds and their extract that modulates the pathological EMT or its deleterious effects, through acting on different cellular signal transduction pathways both in vivo and in vitro. Thereby, cryptotanshinone, resveratrol, oxymatrine, ligustrazine, osthole, codonolactone, betanin, tannic acid, gentiopicroside, curcumin, genistein, paeoniflorin, gambogic acid and Cinnamomum cassia extracts inhibit EMT acting on transforming growth factor-β (TGF-β)/Smads signaling pathways. Gedunin, carnosol, celastrol, black rice anthocyanins, Duchesnea indica, cordycepin and Celastrus orbiculatus extract downregulate vimectin, fibronectin and N-cadherin. Sulforaphane, luteolin, celastrol, curcumin, arctigenin inhibit β-catenin signaling pathways. Salvianolic acid-A and plumbagin block oxidative stress, while honokiol, gallic acid, piperlongumine, brusatol and paeoniflorin inhibit EMT transcription factors such as SNAIL, TWIST and ZEB. Plectranthoic acid, resveratrol, genistein, baicalin, polyphyllin I, cairicoside E, luteolin, berberine, nimbolide, curcumin, withaferin-A, jatrophone, ginsenoside-Rb1, honokiol, parthenolide, phoyunnanin-E, epicatechin-3-gallate, gigantol, eupatolide, baicalin and baicalein and nitidine chloride inhibit EMT acting on other signaling pathways (SIRT1, p38 MAPK, NFAT1, SMAD, IL-6, STAT3, AQP5, notch 1, PI3K/Akt, Wnt/β-catenin, NF-κB, FAK/AKT, Hh). Despite the huge amount of preclinical data regarding EMT modulation by the natural compounds of plant, clinical translation is poor. Additionally, this review highlights some relevant examples of clinical trials using natural plant compounds to modulate EMT and its deleterious effects. Overall, this opens up new therapeutic alternatives in cancer, inflammatory and fibrosing diseases through the control of EMT process.

Resveratrol Promotes Diabetic Wound Healing via SIRT1-FOXO1-c-Myc Signaling Pathway-Mediated Angiogenesis.

Abstract: Background/Aims: Diabetic non-healing skin ulcers represent a serious challenge in clinical practice, in which the hyperglycemia-induced disturbance of angiogenesis, and endothelial dysfunction play a crucial role. Resveratrol (RES), a silent information regulator 1 (SIRT1) agonist, can improve endothelial function and has strong pro-angiogenic properties, and has thus become a research focus for the treatment of diabetic non-healing skin ulcers; however, the underlying mechanism by which RES regulates these processes remains unclear. Therefore, the present study was intended to determine if RES exerts its observed protective role in diabetic wound healing by alleviating hyperglycemia-induced endothelial dysfunction and the disturbance of angiogenesis. Methods: We investigated the effects of RES on cell migration, cell proliferation, apoptosis, tube formation, and the underlying molecular mechanisms in 33 mM high glucose-stimulated human umbilical vein endothelial cells (HUVECs) by semi-quantitative RT-PCR, western blot analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and immunofluorescence in vitro. We further explored the role of RES on endothelial dysfunction and wound healing disturbance in db/db mice by TUNEL staining, immunofluorescence, and photography in vivo. Results: We observed an obvious inhibition of hyperglycemia-triggered endothelial dysfunction and a disturbance of angiogenesis, followed by the promotion of diabetic wound healing via RES, along with restoration of the activity of the hyperglycemia-impaired SIRT1 signaling pathway. Pretreatment with EX-527, a SIRT1 inhibitor, abolished the RES-mediated endothelial protection and pro-angiogenesis action, and then delayed diabetic wound healing. Furthermore, examination of the overexpression of forkhead box O1 (FOXO1), a transcription factor substrate of SIRT1, in HUVECs and db/db mice revealed that RES activated SIRT1 to restore hyperglycemia-triggered endothelial dysfunction and disturbance of angiogenesis, followed by the promotion of diabetic wound healing in a c-Myc-dependent manner. Pretreatment with 10058-F4, a c-Myc inhibitor, repressed RES-mediated endothelial protection, angiogenesis, and diabetic wound healing. Conclusion: Our findings indicate that the positive role of RES in diabetic wound healing via its SIRT1-dependent endothelial protection and pro-angiogenic effects involves the inhibition of FOXO1 and the de-repression of c-Myc expression.