Multifaceted applications of ulvan polysaccharides: Insights on biopharmaceutical avenues.

Ulvans are water-soluble sulfated polysaccharides predominantly found in the cell wall of green algae. They hold unique characteristics that are attributed to their 3D conformation, functional groups along with the presence of saccharides and sulfate ions. Traditionally, ulvans are widely used as food supplements and probiotics owing to the high content of carbohydrates. Despite their widespread usage in food industry, an in-depth understanding is required for extrapolating their potential application as a nutraceutical and medicinal agent which could be beneficial in promoting human health and well-being. This review emphasizes novel therapeutic avenues where ulvan polysaccharides can be used beyond their nutritional applications. A collection of literature points towards multifarious applications of ulvan in various biomedical fields. Structural aspects along with extraction and purification methods have been discussed. The underlying molecular mechanisms associated with its biomedical potential in different therapeutic fields like oncology, infectious diseases, inflammation, neuroprotection and tissue engineering, etc. have been unravelled. Challenges associated with clinical translation and future perspectives have been deliberated.

Organoids in modelling infectious diseases.

Approaches based on animal and two-dimensional (2D) cell culture models cannot ensure reliable results in modeling novel pathogens or in drug testing in the short term; therefore, there is rising interest in platforms such as organoids. To develop a toolbox that can be used successfully to overcome current issues in modeling various infections, it is essential to provide a framework of recent achievements in applying organoids. Organoids have been used to study viruses, bacteria, and protists that cause, for example, respiratory, gastrointestinal, and liver diseases. Their future as models of infection will be associated with improvements in system complexity, including abilities to model tissue structure, a dynamic microenvironment, and coinfection. Teaser. Organoids are a flexible tool for modelling viral, bacterial and protist infections. They can provide fast and reliable information on the biology of pathogens and in drug screening, and thus have become essential in combatting emerging infectious diseases.

Emerging technologies and infection models in cellular microbiology.

The field of cellular microbiology, rooted in the co-evolution of microbes and their hosts, studies intracellular pathogens and their manipulation of host cell machinery. In this review, we highlight emerging technologies and infection models that recently promoted opportunities in cellular microbiology. We overview the explosion of microscopy techniques and how they reveal unprecedented detail at the host-pathogen interface. We discuss the incorporation of robotics and artificial intelligence to image-based screening modalities, biochemical mapping approaches, as well as dual RNA-sequencing techniques. Finally, we describe chips, organoids and animal models used to dissect biophysical and in vivo aspects of the infection process. As our knowledge of the infected cell improves, cellular microbiology holds great promise for development of anti-infective strategies with translational applications in human health.

The Health Benefits of Emodin, a Natural Anthraquinone Derived from Rhubarb-A Summary Update.

Emodin (6-methyl-1,3,8-trihydroxyanthraquinone) is a naturally occurring anthraquinone derivative found in roots and leaves of various plants, fungi and lichens. For a long time it has been used in traditional Chinese medicine as an active ingredient in herbs. Among other sources, it is isolated from the rhubarb Rheum palmatum or tuber fleece-flower Polygonam multiflorum. Emodin has a wide range of biological activities, including diuretic, antibacterial, antiulcer, anti-inflammatory, anticancer and antinociceptive. According to the most recent studies, emodin acts as an antimalarial and antiallergic agent, and can also reverse resistance to chemotherapy. In the present work the potential therapeutic role of emodin in treatment of inflammatory diseases, cancers and microbial infections is analysed.

Managing Anemia across the Stages of Kidney Disease in Those Hyporesponsive to Erythropoiesis-Stimulating Agents.

BACKGROUND: Patients with CKD frequently have anemia that results from iron-restricted erythropoiesis and inflammation. Anemia of CKD is currently managed with iron supplements and erythropoiesis-stimulating agents (ESAs) to promote erythropoiesis and with RBC transfusion in severe cases. Hyporesponse to ESAs, or the need for larger than usual doses to attain a given hemoglobin (Hb) level, is associated with increased morbidity and mortality and presents a pressing clinical challenge, particularly for patients on dialysis. This paper reviews ESA hyporesponse and potential new therapeutic options in the management of anemia of CKD. SUMMARY: The most common causes of ESA hyporesponse include iron deficiency and inflammation, and to a lesser degree, secondary hyperparathyroidism, inadequate dialysis, malnutrition, and concomitant medications. Management of ESA hyporesponse is multipronged and involves treating low level infections, ensuring adequate nutrition, and optimizing iron status and dialysis modality, although some patients can remain refractory. Inflammation directly increases production and secretion of hepcidin, contributes to an impaired response to hypoxia, and suppresses proliferation of erythroid progenitors. Coordination of renal and hepatic erythropoietin (EPO) production and iron metabolism is under the control of hypoxia-inducible factors (HIF), which are in turn regulated by HIF-prolyl hydroxylases (HIF-PHs). HIF-PHs and hepcidin are therefore attractive potential drug targets particularly in patients with ESA hyporesponse. Several oral HIF-PH inhibitors have been evaluated in patients with anemia of CKD and have been shown to increase Hb and reduce hepcidin regardless of inflammation, iron status, or dialysis modality. These sustained effects are achieved through more modest increases in endogenous EPO compared with ESAs. Key Messages: Treatments that address ESA hyporesponse remain a significant unmet clinical need in patients with anemia of CKD. New therapies such as HIF-PH inhibitors have the potential to address fundamental aspects of ESA hyporesponse and provide a new therapeutic option in these patients.

Antibiotic guidelines coupled with selective reporting of antibiograms.

OBJECTIVES: We reported the impact of internal guidelines coupled with selective reporting of antibiotic susceptibility tests (srAST) on antibiotic adequacy in healthcare facilities. METHODS: This prospective study involved clinicians from three clinics with medical and surgical activities employing a full-time infectious disease (ID) specialist. Internal guidelines were updated in 2016. The clinics were working with the same laboratory, which delivered the srAST introduced in March 2017. Two weeks per month over a 6-month period, all isolated bacterial specimens, empirical antibiotic therapies (EAT) and the documented ones were analyzed. An EAT listed in the guidelines and a documented therapy mentioned in the srAST defined their adequacy. RESULTS: A total of 257 positive bacterial samples were analyzed in 199 patients, for which 106 infections were studied. Of these, 32% were urinary tract infections, 15% were primary bloodstream infections, 11% were bone infections, and 42% were other types of infection. The three main bacteria were Escherichia coli (27%), Staphylococcus aureus (24%), and Enterococcus faecalis (14%). The total number of antibiotic prescriptions was 168, with 75 (45%) EATs and 93 (55%) documented therapies. There were 35/75 (47%) adequate EATs and 86/93 (92%) adequate documented therapies. The ID specialist was not involved in 90/168 (53.5%) prescriptions, of which 43/90 (48%) were adequate, with 21/35 (60%) EATs and 22/86 (25%) documented therapies. There was a statistical correlation between compliance of the EATs with guidelines and of the documented therapy with srAST (p=0.02). CONCLUSION: Combining internal guidelines and srAST led to a high rate of antibiotic adequacy.

Tea bioactive components prevent carcinogenesis via anti-pathogen, anti-inflammation, and cell survival pathways.

Cancer seriously impairs human health and survival. Many perturbations, such as increased oxidative stress, pathogen infection, and inflammation, promote the accumulation of DNA mutations, and ultimately lead to carcinogenesis. Tea is one of the most highly consumed beverages worldwide and has been linked to improvements in human health. Tea contains many active components, including tea polyphenols, tea polysaccharides, L-theanine, tea pigments, and caffeine among other common components. Several studies have identified components in tea that can directly or indirectly reduce carcinogenesis with some being used in a clinical setting. Many previous studies, in vitro and in vivo, have focused on the mechanisms that functional components of tea utilized to protect against cancer. One particular mechanism that has been well described is an improvement in antioxidant capacity seen with tea consumption. However, other mechanisms, including anti-pathogen, anti-inflammation and alterations in cell survival pathways, are also involved. The current review focuses on these anti-cancer mechanisms. This will be beneficial for clinical utilization of tea components in preventing and treating cancer in the future.

Rhinacanthus nasutus "Tea" Infusions and the Medicinal Benefits of the Constituent Phytochemicals.

Rhinacanthus nasutus (L.) Kurz (Acanthaceae) (Rn) is an herbaceous shrub native to Thailand and much of South and Southeast Asia. It has several synonyms and local or common names. The root of Rn is used in Thai traditional medicine to treat snake bites, and the roots and/or leaves can be made into a balm and applied to the skin for the treatment of skin infections such as ringworm, or they may be brewed to form an infusion for the treatment of inflammatory disorders. Rn leaves are available to the public for purchase in the form of "tea bags" as a natural herbal remedy for a long list of disorders, including diabetes, skin diseases (antifungal, ringworm, eczema, scurf, herpes), gastritis, raised blood pressure, improved blood circulation, early-stage tuberculosis antitumor activity, and as an antipyretic. There have been many studies investigating the roles of Rn or compounds isolated from the herb regarding diseases such as Alzheimer's and other neurodegenerative diseases, cancer, diabetes and infection with bacteria, fungi or viruses. There have, however, been no clinical trials to confirm the efficacy of Rn in the treatment of any of these disorders, and the safety of these teas over long periods of consumption has never been tested. This review assesses the recent research into the role of Rn and its constituent compounds in a range of diseases.

Going Beyond Antibiotics: Natural Plant Extracts as an Emergent Strategy to Combat Biofilm-Associated Infections.

Biofilms are a collective of multiple types of bacteria that develop on a variety of surfaces. Biofilm development results in heightened resistance to antibiotics. Quorum sensing plays an important role in biofilm development as it is one of the common communication mechanisms within cells, which balances and stabilizes the environment, when the amount of bacteria increases. Because of the important implications of the roles biofilms play in infectious diseases, it is crucial to investigate natural antibacterial agents that are able to regulate biofilm formation and development. Various studies have suggested that natural plant products have the potential to suppress bacterial growth and exhibit chemopreventive traits in the modulation of biofilm development. In this review, we discuss and collate potential antibiofilm drugs and biological molecules from natural sources, along with their underlying mechanisms of action. In addition, we also discuss the antibiofilm drugs that are currently under clinical trials and highlight their potential future uses.

Chemical Evaluation of the Effects of Storage Conditions on the Botanical Goldenseal using Marker-based and Metabolomics Approaches.

Hydrastis canadensis, commonly known as goldenseal, is a botanical native to the southeastern United States that has been used for the treatment of infection. The activity of goldenseal is often attributed to the presence of alkaloids (cyclic, nitrogen-containing compounds) present within its roots. Chemical components of botanical supplements like goldenseal may face degradation if not stored properly. The purpose of the research was to analyze the stability of known and unknown metabolites of H. canadensis during exposure to different storage conditions using mass spectrometry. Three abundant metabolites of H. canadensis, berberine, canadine, and hydrastine, were chosen for targeted analysis, and the stability of unknown metabolites was evaluated using untargeted metabolomics. The analysis and evaluation of H. canadensis samples were performed utilizing LC-MS and Principal Component Analysis (PCA). The research project focused on identifying the chemical changes in the metabolite content of H. canadensis under different temperature conditions (40°C ± 5°C, 20°C ± 5°C , and 4°C ± 5°C), different light:dark (hr:hr) cycles (16:8, 12:12, and 0:24), and different sample conditions (powdered roots versus whole roots) over a six month period. The results of this 6-month study revealed that the storage conditions evaluated had no significant effects on the chemical composition of H. canadensis roots. Hence, as long as H. canadensis roots are stored within the storage conditions tested in the study, no significant changes in chemical compositions of metabolites are expected.

Vaccines Against Antimicrobial Resistance.

In the last century, life expectancy has increased considerably, thanks to the introduction of antibiotics, hygiene and vaccines that have contributed to the cure and prevention of many infectious diseases. The era of antimicrobial therapy started in the nineteenth century with the identification of chemical compounds with antimicrobial properties. However, immediately after the introduction of these novel drugs, microorganisms started to become resistant through different strategies. Although resistance mechanisms were already present before antibiotic introduction, their large-scale use and mis-use have increased the number of resistant microorganisms. Rapid spreading of mobile elements by horizontal gene transfer such as plasmids and integrative conjugative elements (ICE) carrying multiple resistance genes has dramatically increased the worldwide prevalence of relevant multi drug-resistant human pathogens such as Staphylococcus aureus, Neisseria gonorrhoeae, and Enterobacteriaceae. Today, antimicrobial resistance (AMR) remains one of the major global concerns to be addressed and only global efforts could help in finding a solution. In terms of magnitude the economic impact of AMR is estimated to be comparable to that of climate global change in 2030. Although antibiotics continue to be essential to treat such infections, non-antibiotic therapies will play an important role in limiting the increase of antibiotic resistant microorganisms. Among non-antibiotic strategies, vaccines and therapeutic monoclonal antibodies (mAbs) play a strategic role. In this review, we will summarize the evolution and the mechanisms of antibiotic resistance, and the impact of AMR on life expectancy and economics.

Antimicrobial Terpenoids as a Potential Substitute in Overcoming Antimicrobial Resistance.

There was a golden era where everyone thought that microbes can no longer establish threat to humans but the time has come where microbes are proposing strong resistance against the majority of antimicrobials. Over the years, the inappropriate use and easy availability of antimicrobials have made antimicrobial resistance (AMR) to emerge as the world's third leading cause of death. Microorganisms over the time span have acquired resistance through various mechanisms such as efflux pump, transfer through plasmids causing mutation, changing antimicrobial site of action, or modifying the antimicrobial which will lead to become AMR as the main cause of death worldwide by 2030. In order to overcome the emerging resistance against majority of antimicrobials, there is a need to uncover drugs from plants because they have proved to be effective antimicrobials due to the presence of secondary metabolites such as terpenoids. Terpenoids abundant in nature are produced in response to microbial attack have huge potential against various microorganisms through diverse mechanisms such as membrane disruption, anti-quorum sensing, inhibition of protein synthesis and ATP. New approaches like combination therapy of terpenoids and antimicrobials have increased the potency of treatment against various multidrug resistant microorganisms by showing synergism to each other.

Omics strategies decipher therapeutic discoveries of traditional Chinese medicine against different diseases at multiple layers molecular-level.

Traditional Chinese medicine (TCM) has been broadly used for the personalized treatment of many diseases in China for thousands of years. In the past century, TCM was also introduced to other Asian countries and even the Western world. Increasing evidence has shown that TCM has the capacity to treat numerous complex diseases in the clinic, such as cardiovascular diseases (CVDs), infectious diseases, metabolic diseases, and neurodegenerative diseases. However, the earlier lack of analytical strategies to annotate the chemical complexity has severely impeded the modern study and translational application of TCM. This critical review aims to explore and exploit applications of systems biology-driven omics methods in TCM against a diversity of diseases, toward the specific use of TCM to treat patients with different diseases. Such effort shall enhance the applicability of systems biology-driven omics strategies in deciphering the mechanisms by which TCM treats different diseases and may lead to the discovery of new therapeutic directions. In addition, we proposed the possible strategies to innovate the applicable pattern of omics technologies in TCM niches, such as precision-modification metabolomics and chinmedomics methods, allowing to unveil the complexity of TCM, which must enable TCM to serve better for the population-health. Taken together, this review eventually shall highlight the core value of omics technologies in innovating TCM to combat the diseases in a new horizon.

The pharmacology and therapeutic applications of monoclonal antibodies.

Monoclonal antibodies (mAbs) have emerged as a major class of therapeutic agents on the market. To date, approximately 80 mAbs have been granted marketing approval. In 2018, 12 new mAbs were approved by the FDA, representing 20% of the total number of approved drugs. The majority of mAb therapeutics are for oncological and immunological/infectious diseases, but these are expanding into other disease areas. Over 100 monoclonal antibodies are in development, and their unique features ensure that these will remain a part of the therapeutic pipeline. Thus, the therapeutic value and the elucidation of their pharmacological properties supporting clinical development of these large molecules are unquestioned. However, their utilization as pharmacological tools in academic laboratories has lagged behind their small molecule counterparts. Early therapeutic mAbs targeted soluble cytokines, but now that mAbs also target membrane-bound receptors and have increased circulating half-life, their pharmacology is more complex. The principles of pharmacology have enabled the development of high affinity, potent and selective small molecule therapeutics with reduced off-target effects and drug-drug interactions. This review will discuss how the same basic principles can be applied to mAbs, with some important differences. Monoclonal antibodies have several benefits, such as fewer off-target adverse effects, fewer drug-drug interactions, higher specificity, and potentially increased efficacy through targeted therapy. Modifications to decrease the immunogenicity and increase the efficacy are described, with examples of optimizing their pharmacokinetic properties and enabling oral bioavailability. Increased awareness of these advances may help to increase their use in exploratory research and further understand and characterize their pharmacological properties.

Therapeutic Effects of Curcumin-From Traditional Past to Present and Future Clinical Applications.

The efficacy of the plant-derived polyphenol curcumin, in various aspects of health and wellbeing, are a matter of public interest. An internet search of the term "Curcumin" displays about 12 million hits. Among the multitudinous information presented on partly doubtful websites, there are reports attracting the reader with promises ranging from eternal youth to cures for incurable diseases. Unfortunately, many of these reports are not based on scientific evidence, but they feed the desideratum of the reader for a "miracle cure". This circumstance makes it very difficult for researchers, whose work is scientifically sound and evidence is based on the therapeutic benefits (or side effects) of curcumin, to demarcate their results from sensational reports that circulate in the web and in other media. This is only one of many obstacles making it difficult to pave curcumin's way into clinical application; others are its nonpatentability and low economic usability. A further impediment comes from scientists who never worked with curcumin or any other natural plant-derived compound in their own labs. They have never tested these compounds in any scientific assay, neither in vitro nor in vivo; however, they claim, in a sometimes polemic manner, that everything that has so far been published on curcumin's molecular effects is based on artefacts. The here presented Special Issue comprises a collection of five scientifically sound articles and nine reviews reporting on the therapeutic benefits and the molecular mechanisms of curcumin or of chemically modified curcumin in various diseases ranging from malignant tumors to chronic diseases, microbial infection, and even neurodegenerative diseases. The excellent results of the scientific projects that underlie the five original papers give reason to hope that curcumin will be part of novel treatment strategies in the near future-either as monotherapy or in combination with other drugs or therapeutic applications.

Effect of antimicrobial stewardship with rapid MALDI-TOF identification and Vitek 2 antimicrobial susceptibility testing on hospitalization outcome.

We sought to evaluate time for bacterial culture and initiation of appropriate therapy for patients, from 2017 (without rapid diagnostic test (RDT) and Antimicrobial Stewardship Program (ASP)) and 2018 (with RDT and ASP). Time to identification (ID) was significantly faster in 2018 (2018 24.9 ±â€¯14.4, 2017 33.8 ±â€¯17 h, P = 0.001). Time to antimicrobial susceptibility test (AST) results was significantly faster for patients in 2018 compared to 2017 (18.2 ±â€¯14 h compared to 28.5 ±â€¯14.9 h, P < 0.001). Length of hospital stay for enrolled patients was significantly shorter in 2018 compared to 2017 (2018 10.7 ±â€¯11.1 days and 2017 15.5 ±â€¯18.1 days, P = 0.05). Length of antimicrobial therapy for enrolled patients was significantly shorter for 2018 (2018 6.7 ±â€¯3.8 d vs. 2017 8.8 ±â€¯7.8 d, P = 0.036). These results demonstrate MALDI-TOF/Vitek 2 leads to an average 21.5 h faster ID and AST results that can be acted upon by ASP for antimicrobial recommendations.

Integrated outpatient treatment of opioid use disorder and injection-related infections: A description of a new care model.

Persons with opioid use disorder (OUD) hospitalized with severe, injection-related infections (SIRI) are frequently hospitalized for the duration of IV antibiotic treatment due to concerns regarding their eligibility for outpatient parenteral antimicrobial therapy (OPAT), which is the standard of care for prolonged IV antibiotic courses for patients without drug use. As part of a pilot study, a novel, integrated care model was developed where patients with OUD and SIRI receive addiction consultation and buprenorphine induction while hospitalized, followed by ongoing management in an outpatient clinic that combines office-based opioid treatment with buprenorphine pharmacotherapy and counseling services with OPAT. Through three illustrative case vignettes the outpatient model is described along with challenges, lessons learned and future directions.

Aminoacyl-tRNA synthetases as therapeutic targets.

Aminoacyl-tRNA synthetases (ARSs) are essential enzymes for protein synthesis with evolutionarily conserved enzymatic mechanisms. Despite their similarity across organisms, scientists have been able to generate effective anti-infective agents based on the structural differences in the catalytic clefts of ARSs from pathogens and humans. However, recent genomic, proteomic and functionomic advances have unveiled unexpected disease-associated mutations and altered expression, secretion and interactions in human ARSs, revealing hidden biological functions beyond their catalytic roles in protein synthesis. These studies have also brought to light their potential as a rich and unexplored source for new therapeutic targets and agents through multiple avenues, including direct targeting of the catalytic sites, controlling disease-associated protein-protein interactions and developing novel biologics from the secreted ARS proteins or their parts. This Review addresses the emerging biology and therapeutic applications of human ARSs in diseases including autoimmune and rare diseases, and cancer.

Optimization of ionic liquid-incorporated PLGA nanoparticles for treatment of biofilm infections.

Ionic liquids (ILs) containing imidazolium cations have a number of useful properties, such as high permeability to cells, high antimicrobial activity, and good biocompatibility. With the aid of ILs, transdermal delivery, solubilization of poorly soluble drugs were developed and therapeutic effects were improved. In this work, 1­butyl­3­methylimidazolium hexafluorophosphate-incorporated, chitosan-modified, submicron-sized poly(dl­lactide­co­glycolide) (PLGA) nanoparticles (NPs) were prepared using the emulsion solvent diffusion method for the treatment of biofilm infections. Prepared IL-incorporated PLGA NPs using surfactants such as Tween-80 and poloxamer-188 showed a high antibacterial activity to the bacterial cells under the biofilm. Additionally, antibacterial mechanism of IL-incorporated PLGA NPs was revealed by annular dark field scanning transmission electron microscopy combined a simple sample pretreatment method. We established a drug delivery system using IL-incorporated PLGA NPs to enhance the potential of polymeric nanocarriers for treating biofilm infections.

Vitamin D deficiency and treatment versus risk of infection in end-stage renal disease patients under dialysis: a systematic review and meta-analysis.

Background: Infections are common and can be fatal in patients undergoing long-term dialysis. Recent studies have shown conflicting evidence associating infection with vitamin D status or use of vitamin D and have not been systematically reviewed in this population. Methods: We searched PubMed, Web of Science, Cochrane Library, Embase and three Chinese databases from inception until December 2017 for interventional [non-randomized or randomized controlled trials (RCTs)], cohort and case-control studies on levels of serum 25-hydroxyvitamin D [25(OH)D] or use of vitamin D [supplemental nutritional vitamin D or vitamin D receptor activator (VDRA)] and infection (any infection, infection-required hospitalization or infection-related death or composite) in long-term dialysis patients. We conducted a meta-analysis on the relative risk (RR) of infection and level of 25(OH)D or use of vitamin D. Results: Of 2440 reports identified, 17 studies met inclusion criteria, all with moderate quality, with 6 cohort studies evaluating 25(OH)D serum concentrations (n = 5714) and 11 (2 RCTs and 9 observational studies) evaluating the use of vitamin D (n = 92 309). The risk of composite infection was 39% lower {relative risk [RR] 0.61 [95% confidence interval (CI) 0.41-0.89]} in the subjects with high or normal levels of 25(OH)D than in those with low levels. When compared with those who did not use vitamin D, the pooled adjusted risk for composite infection was 41% lower in those who used vitamin D [RR 0.59 (95% CI 0.43-0.81)]. Conclusions: High or normal serum levels of 25(OH)D and the use of vitamin D, particularly VDRA, were each associated with a lower risk of composite infection in long-term dialysis patients.