DRAMP 3.0: an enhanced comprehensive data repository of antimicrobial peptides.

Stapled antimicrobial peptides are an emerging class of artificial cyclic peptide molecules which have antimicrobial activity and potent structure stability. We previously published the Data Repository of Antimicrobial Peptides (DRAMP) as a manually annotated and open-access database of antimicrobial peptides (AMPs). In the update of version 3.0, special emphasis was placed on the new development of stapled AMPs, and a subclass of specific AMPs was added to store information on these special chemically modified AMPs. To help design low toxicity AMPs, we also added the cytotoxicity property of AMPs, as well as the expansion of newly discovered AMP data. At present, DRAMP has been expanded and contains 22259 entries (2360 newly added), consisting of 5891 general entries, 16110 patent entries, 77 clinical entries and 181 stapled AMPs. A total of 263 entries have predicted structures, and more than 300 general entries have links to experimentally determined structures in the Protein Data Bank. The update also covers new annotations, statistics, categories, functions and download links. DRAMP is available online at http://dramp.cpu-bioinfor.org/.

Classification, structure and mechanism of antiviral polysaccharides derived from edible and medicinal fungus.

The deficiency of chemical-synthesized antiviral drugs when applied in clinical therapy, such as drug resistance, and the lack of effective antiviral drugs to treat some newly emerging virus infections, such as COVID-19, promote the demand of novelty and safety anti-virus drug candidate from natural functional ingredient. Numerous studies have shown that some polysaccharides sourcing from edible and medicinal fungus (EMFs) exert direct or indirect anti-viral capacities. However, the internal connection of fungus type, polysaccharides structural characteristics, action mechanism was still unclear. Herein, our review focus on the two aspects, on the one hand, we discussed the type of anti-viral EMFs and the structural characteristics of polysaccharides to clarify the structure-activity relationship, on the other hand, the directly or indirectly antiviral mechanism of EMFs polysaccharides, including virus function suppression, immune-modulatory activity, anti-inflammatory activity, regulation of population balance of gut microbiota have been concluded to provide a comprehensive theory basis for better clinical utilization of EMFs polysaccharides as anti-viral agents.

Beyond Hot and Spicy: TRPV Channels and their Pharmacological Modulation.

Transient receptor potential vanilloid (TRPV) channels are part of the TRP channel superfamily and named after the first identified member TRPV1, that is sensitive to the vanillylamide capsaicin. Their overall structure is similar to the structure of voltage gated potassium channels (Kv) built up as homotetramers from subunits with six transmembrane helices (S1-S6). Six TRPV channel subtypes (TRPV1-6) are known, that can be subdivided into the thermoTRPV (TRPV1-4) and the Ca2+-selective TRPV channels (TRPV5, TRPV6). Contrary to Kv channels, TRPV channels are not primary voltage gated. All six channels have distinct properties and react to several endogenous ligands as well as different gating stimuli such as heat, pH, mechanical stress, or osmotic changes. Their physiological functions are highly diverse and subtype as well as tissue specific. In many tissues they serve as sensors for different pain stimuli (heat, pressure, pH) and contribute to the homeostasis of electrolytes, the maintenance of barrier functions and the development of macrophages. Due to their fundamental role in manifold physiological and pathophysiological processes, TRPV channels are promising targets for drug development. However, drugs targeting specific TRPV channels, that are suitable for drug therapy, are rare. Moreover, selective and potent compounds for further research at TRPV channels are often lacking. In this review different aspects of the structure, the different gating stimuli, the expression pattern, the physiological and pathophysiological roles as well as the modulating mechanisms of synthetic, natural and endogenous ligands are summarized.

Occurrence and possible roles of polysaccharides in fungi and their influence on the development of new technologies.

The article summarizes the roles of polysaccharides in the biology of fungi and their relationship in the development of new technologies. The comparative approach between the evolution of fungi and the chemistry of glycobiology elucidated relevant aspects about the role of polysaccharides in fungi. Also, based on the knowledge of fungal glycobiology, it was possible to address the development of new technologies, such as the production of new anti-tumor drugs, vaccines, biomaterials, and applications in the field of robotics. We conclude that polysaccharides activate pathways of apoptosis, secretion of pro-inflammatory substances, and macrophage, inducing anticancer activity. Also, the activation of the immune system, which opens the way for the production of vaccines. The development of biomaterials and parts for robotics is a promising and little-explored field. Finally, the article is multidisciplinary, with a different and integrated approach to the role of nature in the sustainable development of new technologies.

Pharmaco-Immunomodulatory Therapy in COVID-19.

The severe acute respiratory syndrome coronavirus 2 associated coronavirus disease 2019 (COVID-19) illness is a syndrome of viral replication in concert with a host inflammatory response. The cytokine storm and viral evasion of cellular immune responses may play an equally important role in the pathogenesis, clinical manifestation, and outcomes of COVID-19. Systemic proinflammatory cytokines and biomarkers are elevated as the disease progresses towards its advanced stages, and correlate with worse chances of survival. Immune modulators have the potential to inhibit cytokines and treat the cytokine storm. A literature search using PubMed, Google Scholar, and ClinicalTrials.gov was conducted through 8 July 2020 using the search terms 'coronavirus', 'immunology', 'cytokine storm', 'immunomodulators', 'pharmacology', 'severe acute respiratory syndrome 2', 'SARS-CoV-2', and 'COVID-19'. Specific immune modulators include anti-cytokines such as interleukin (IL)-1 and IL-6 receptor antagonists (e.g. anakinra, tocilizumab, sarilumab, siltuximab), Janus kinase (JAK) inhibitors (e.g. baricitinib, ruxolitinib), anti-tumor necrosis factor-α (e.g. adalimumab, infliximab), granulocyte-macrophage colony-stimulating factors (e.g. gimsilumab, lenzilumab, namilumab), and convalescent plasma, with promising to negative trials and other data. Non-specific immune modulators include human immunoglobulin, corticosteroids such as dexamethasone, interferons, statins, angiotensin pathway modulators, macrolides (e.g. azithromycin, clarithromycin), hydroxychloroquine and chloroquine, colchicine, and prostaglandin D2 modulators such as ramatroban. Dexamethasone 6 mg once daily (either by mouth or by intravenous injection) for 10 days may result in a reduction in mortality in COVID-19 patients by one-third for patients on ventilators, and by one-fifth for those receiving oxygen. Research efforts should focus not only on the most relevant immunomodulatory strategies but also on the optimal timing of such interventions to maximize therapeutic outcomes. In this review, we discuss the potential role and safety of these agents in the management of severe COVID-19, and their impact on survival and clinical symptoms.

Cytokine storm and the prospects for immunotherapy with COVID-19.

Knowledge about the pathobiology of SARS-CoV-2 as it interacts with immune defenses is limited. SARS-CoV-2 is spread by droplets that come into contact with mucous membranes. COVID-19 is characterized by 2 or 3 stages: most patients who recover experience 2 stages of illness commencing with an asymptomatic or paucisymptomatic incubation period, followed by a nonsevere symptomatic illness lasting for several weeks, occurring in about 80% of those infected. In the remainder, a third phase marked by a severe respiratory illness, often accompanied by multisystem dysfunction, coagulopathy, and shock is observed. This phase of the illness is characterized by hypercytokinemic inflammation and is often referred to as "cytokine storm." While the immunopathogenesis remains unclear, prospects of treating this severe phase of the illness with immunotherapy are evolving, with some treatments showing promise.

Medication beliefs in first-line and second-line treated multiple sclerosis patients.

BACKGROUND: Immune treatments of multiple sclerosis (MS) can be classified in first-line and second-line approaches. While in both treatment efficacy is often not easy to assess in the short-term, treatment and illness beliefs may differ in first-line and second-line treated patients. The current study aimed to assess differential beliefs about medicine and illness perception between these groups based on the hypothesis that they are closely connected to adherence behaviour. METHODS: An online survey through the website of the German MS Society was performed investigating beliefs about immune treatments as well as the patients' illness perceptions with validated questionnaires. Demographic factors, disability and self-reported adherence rates were studied as moderator variables. RESULTS: In total, 630 patients participated. Data of 433 first-line treated and 192 second-line treated patients with MS (PwMS) were analysed. Necessity beliefs and also concerns beliefs were significantly higher in second-line treated PwMS (MANCOVA p =.001 and p =.006) and generally in patients with higher disability, while illness perception did not differ between groups. Self-assessed adherence rates were around 70% for oral treatments and injectables irrespective of first-line or second-line. Nonadherence was below 5% for infusion treatments. However, most patients reported only single omissions. CONCLUSION: The current study reveals differential behavioural attitudes between first-line versus second-line-treated PwMS. However, follow-up studies are needed to further unravel the relationship between behavioural attitudes and treatment adherence.

Cutaneous Lupus Erythematosus: Current and Future Pathogenesis-Directed Therapies.

Cutaneous lupus erythematosus (CLE) is an autoimmune disease of the skin with significant morbidity. Current treatments are often inadequate to control disease and there are no Food and Drug Administration (FDA)-approved therapies for this potentially debilitating disease, underscoring an unmet medical need. Recent insights into disease pathogenesis have implicated innate and adaptive immune components, including type I and type III interferons in the development of CLE. Promising clinical trials based on these insights are now underway. However, the full spectrum of immune cells, cytokines, and environmental triggers contributing to disease remain to be elucidated. In this review, we will highlight the current understanding of CLE immunopathogenesis, the ongoing clinical trial landscape, and provide a framework for designing future therapeutic strategies for CLE based on new insights into disease pathogenesis.

Proyecto internacional INSPIRE: «¿Qué es normal en la leche humana» (II). Compuestos inmunológicos solubles / Project INSPIRE: «What's normal in human milk?» (II). Soluble immune factors

La protección inmunológica del recién nacido depende principalmente de factores inmunitarios maternos proporcionados a través de la leche. Sin embargo, muy pocos estudios han evaluado la variabilidad natural de los diferentes compuestos inmunitarios presentes en la leche humana de mujeres sanas pertenecientes a poblaciones heterogéneas. En este contexto, el objetivo de este trabajo fue la detección y cuantificación de una amplia gama de factores inmunitarios solubles, entre los que se incluyen factores de inmunidad innata (IL-1β, IL-6, IL-12, INFγ, TNFα) y adquirida (IL-2, IL-4, IL-10, IL-13, IL-17), quimioquinas (IL-8, Groα, MCP1, MIP1β), factores de crecimiento (IL-5, IL-7, EGF, G-CSF, GM-CSF, TGFβ2) e inmunoglobulinas (IgA, IgG, IgM), en la leche producida por mujeres sanas de diversas etnias procedentes de distintos entornos geográficos, dietéticos, socioeconómicos y ambientales. A partir de los resultados de este trabajo, pudimos determinar que un grupo de estos factores (IgA, IgG, IgM, EGF, TGFβ2, IL-7, IL-8, Groα y MIP1β) estaba presente en todas o en la mayoría de las muestras recogidas en todas las cohortes y, por tanto, podría considerarse como el núcleo común (core) de la leche humana en condiciones fisiológicas

Newborn immune protection mostly relies on maternal immune factors provided through milk. However, studies dealing with an in-depth profiling of the different immune compounds present in human milk and with the assessment of their natural variation in healthy women from different populations are very scarce. In this context, the objective of this work was the detection and quantification of a wide array of immune compounds, including innate immunity factors (IL-1β, IL-6, IL-12, INFγ, TNFα), acquired immunity factors (IL-2, IL-4, IL-10, IL-13, IL-17), chemokines (IL-8, Groα, MCP1, MIP1β), growth factors (IL-5, IL-7, EGF, G-CSF, GM-CSF, TGFβ2), and immunoglobulins (IgA, IgG, IgM), in milk produced by healthy women of different ethnicities living in different geographic, dietary, socioeconomic, and environmental settings. Among the analyzed factors (IgA, IgG, IgM, EGF, TGFβ2, IL-7, IL-8, Groα, and MIP1β) were detected in all or most of the samples collected in each population and, therefore, this specific set of compounds might be considered as a universal core of soluble immune factors in milk produced by healthy women worldwide

Polyprenyl Phosphates Induce a High Humoral and Cellular Response to Immunization with Recombinant Proteins of the Replicative Complex of the Hepatitis C Virus.

The search for new adjuvants remains the critical task for the creation of hepatitis C vaccines due to the weak immunogenicity of biotechnological products. When immunizing mice with the recombinant proteins NS3 and NS5B of the hepatitis C virus (HCV), the adjuvant activity of three immunomodulators was compared. Phosprenyl® on the basis of polyprenyl phosphate (PPP), chemically synthesized analogue of the bacterial cell wall glucosaminyl muramyl dipeptide (GMDP), and IFN-α recombinant protein were tested. GMDP increased the activity of IgG1 antibodies 4-6 times but did not stimulate the production of IFN-γ; IFN-α has not shown any adjuvant properties. The introduction of recombinant HCV proteins together with PPP in low doses increased the activity of IgG2a isotype antibodies 4-7 times and increased IFN-γ secretion 3 times. Thus, it was first shown that PPP polarizes the immune response to Th1-type and is a promising adjuvant for the development of a vaccine against hepatitis C.

Impact of PCSK9 monoclonal antibodies on circulating hs-CRP levels: a systematic review and meta-analysis of randomised controlled trials.

OBJECTIVE: To evaluate the potential effects of proprotein convertase subtilisin/kexin type 9 monoclonal antibody (PCSK9-mAb) on high-sensitivity C reactive protein (hs-CRP) concentrations. DESIGN: A systematic review and meta-analysis of randomised controlled trials. DATA SOURCES: PubMed, MEDLINE, the Cochrane Library databases, ClinicalTrials.gov and recent conferences were searched from inception to May 2018. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: All randomised controlled trials that reported changes of hs-CRP were included. RESULTS: Ten studies involving 4198 participants were identified. PCSK9-mAbs showed a slight efficacy in reducing hs-CRP (-0.04 mg/L, 95% CI: -0.17 to 0.01) which was not statistically different. The results did not altered when subgroup analyses were performed including PCSK9-mAb types (alirocumab: 0.12 mg/L, 95% CI: -0.18 to 0.43; evolocumab: 0.00 mg/L, 95% CI: -0.07 to 0.07; LY3015014: -0.48 mg/L, 95% CI: -1.28 to 0.32; RG7652: 0.35 mg/L, 95% CI: -0.26 to 0.96), treatment duration (≤12w: 0.00 mg/L, 95% CI: -0.07 to 0.07; >12w: -0.11 mg/L, 95% CI: -0.45 to -0.23), participant characteristics (familial hypercholesterolaemia: 0.00 mg/L, 95% CI: -0.07 to 0.07; non-familial hypercholesterolaemia: 0.07 mg/L, 95% CI: -0.12 to 0.26; mix: -0.48 mg/L, 95% CI: -1.28 to 0.32) and treatment methods (monotherapy: 0.00 mg/L, -0.08 to 0.07; combination therapy: -0.08 mg/L, -0.37 to 0.21). Meta-regression analyses suggested no significant linear correlation between baseline age (p=0.673), sex (p=0.645) and low-density lipoprotein cholesterol reduction (p=0.339). CONCLUSIONS: Our updated meta-analysis suggested that PCSK9-mAbs had no significant impact on circulating hs-CRP levels irrespective of PCSK9-mAb types, participant characteristics and treatment duration or methods.

Comparing treatment options for chronic inflammatory neuropathies and choosing the right treatment plan.

INTRODUCTION: Chronic inflammatory neuropathies are disorders caused by an immune response to peripheral nerve. They include chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy (MMN) and neuropathy associated with anti-MAG IgM monoclonal gammopathy and other less frequent neuropathies. Several immune therapies have been proven to be effective in these neuropathies even if the best therapeutic option is still unsettled. Areas covered: The authors reviewed the literature to compare the efficacy and safety of currently used immune therapies in these neuropathies. The authors also analyzed the effect of other immune suppressive agents and of biological agents including rituximab, eculizumab, natalizumab, alemtuzumab and fingolimod that were found effective in other autoimmune diseases. Expert commentary: Despite the reported efficacy of a number of new immune therapies in some patients with immune mediated neuropathies, their efficacy has not been so far confirmed in randomized controlled studies. High-dose intravenous immunoglobulin (IVIg) (and subcutaneous immunoglobulin [SCIg] for maintenance treatment), steroids and plasma exchange remain the only therapy of proven efficacy in CIDP, IVIg in MMN and, with certain limits, rituximab and, occasionally plasma exchange in neuropathy associated with anti-MAG antibodies. New biological agents are also on the horizon but their efficacy needs to be proved in controlled studies.

[PROINFLAMMATORY CYTOKINES AND SIGNALING PATHWAYS IN PERIPHERAL BLOOD MONONUCLEAR CELLS IN PATIENTS WITH CORONARY ARTERY DISEASE].

Aim: To determine content of mononuclear ells (MNC) in peripheral blood of patients with coronary heart disease (CHD) and factors responsible for their functional state and cytokine production. Materials and methods: Concentration of proteinkinases JNK1/2, ERK1/2, MAPK38, AKT1, JAK2, FAK, AMPK, p70S6K, STAT3, STAT5B and STAT6 was determined in MNC lysate by immune-enzyme assay. Interleukin 1ß, 2, 4 and y-interferon levels were measured in blood sera. Results: In patients with angina of effort and unstable angina, the JNK level was 59,8% and 53,1% higher than the normal one respectively (р=0,013) and (р=0,012). The level of the nuclear transcription factor was 26,9% (р=0,015) and 27,9% (р=0,017), JAK2 31,5% (р=0,022) and 48,6% (р=0,018), STAT3 49,6% (р=0,025) and 55,3% (р=0,02), STAT5B 21,5% (р=0,018) and 30,2% (р=0,011) lower. These changes were associated with a 13,1% (р=0,047) and 51,4% (р=0,019) rise in the STAT6 level, 30,1% (р=0,025) and 79,4% (р=0,003) FAK level, 7,6% (р=0,09) and 15,2% (р=0,039) АКТ1 level, 65,3 (р=0,02) and 76,2% (р=0,017) p70S6K level. Conclusion: Results of the study suggest persistent pro-inflammatory activation of whole blood cells in CHD patients due to enhanced levels of IL-1 and IL-2, components of the MAPK/SAPK signal pathway in MNC and decreased STAT3 level determining cell sensitivity to IL-10. The elevated intracellular level of ERK and JNK us responsible for high responsiveness of MNC to pro-inflammatory cytokines.

Targeted Immunomodulatory Therapy: An Overview.

Monoclonal antibodies and other biologic response modifiers have allowed for targeted drug therapy in managing various autoimmune diseases. A number of immune pathways have been exploited in the development of targeted immunomodulatory therapies, including cytokine-directed therapies such as tumor necrosis factor-alpha and interleukins, integrins, B-cells, and co-stimulation modulators. With new targeted therapies in the pipeline, more options are becoming available for treatment of autoimmune diseases. [Full article available at http://rimed.org/rimedicaljournal-2016-12.asp].

[BASIC PRINCIPLES AND METHODS TO THE USE IMMUNOMODULATING PREPARATIONS IN CLINICAL PRACTICE: CLASSIFICATION, INDICATIONS AND CONTRAINDICATIONS].

This paper is devoted to one of the most pressing issues in modern clinical medicine, the problem of immunomodulators and immunotropic therapy. The materials presented are the logical sequel of the papers published by Revaz I. Sepiashvili in 2001-2015. In these articles, the author proposed the first classification of immunotropic preparations, a brief historical background and chronological emergence of the concept of therapies, as well as definition of immunomodulators. This paper presents an updated classification of immunomodulatory drugs which is valid for January 2015. The paper also outlines basic principles for therapies that allow the clinician not only to select a proper immunomodulator but also to develop strategy and tactics in treatment of the patient, taking into account his/her individual characteristics and the need to use in clinical practice only officially registered immunotropic preparations.

Molecular cloning and functional characterization of a short peptidoglycan recognition protein (HcPGRPS1) from the freshwater mussel, Hyriopsis cumingi.

Peptidoglycan recognition proteins (PGRPs), which are evolutionarily conserved from invertebrates to vertebrates, function as pattern-recognition and effector molecules in innate immunity. In the present study, a short-form PGRP, designated as HcPGRPS1 was identified from freshwater mussel Hyriopsis cumingi. The deduced amino acid sequence of HcPGRPS1 is composed of 235 residues which contains a conserved PGRP domain at the C-terminus. Sequence analysis showed that HcPGRPS1 shared high identities with other known PGRPs. The mRNA of HcPGRPS1 is constitutively expressed in a wide range of all tested tissues, with highest expression level in hepatopancreas, and its expression in tissues (gonad, nephridium, gill and foot) was up-regulated significantly after LPS or PGN stimulation (P<0.05). The recombinant protein of HcPGRPS1 exhibited binding activity and peptidoglycan-lytic amidase activity toward Lys-PGN from Staphylococcus aureus and DAP-PGN from Bacillus subtilis. Furthermore, recombinant HcPGRPS1 displayed strong antibacterial activity to both Gram-negative bacteria Escherichia coli, Aeromonas hydrophila, Aeromonas sobria and Gram-positive bacteria S. aureus in the presence of Zn(2+). These results suggested that HcPGRPS1 plays a multifunctional role in the defense and protection mechanisms of mussel innate immunity against infections.