Immunomodulatory Therapeutics Research Articles

Mesenchymal Stem Cells‐Based Targeting Delivery System: Therapeutic Promises and Immunomodulation against Tumor

AbstractThe inherent homing ability toward tumor sites of mesenchymal stem cells (MSCs) after systemic delivery has, during the past decade, created an impetus to develop these stem cells as living carriers for successful tumor‐targeted therapy. Nevertheless, the controversies about the role of MSCs in promoting or inhibiting tumor progress are impeding the potential clinical application of this system, which is partly due to the contradictory immunomodulation capability. Therefore, in this review, updated progress in the applications of MSCs as the cellular carrier for tumor‐targeting therapy, are summarized. In addition, the immunomodulating capability of MSCs and its influences on tumor progress and metastasis are highlighted. Finally, the advantages and potential risks of MSCs concerning their modulation of immune responses and the factors determining their immune properties are emphasized. It is hoped that the challenges surrounding the impacts on immune response induced by the administration of MSCs summarized in this review will provide a critical guidance for the rational design and proper application of MSCs‐based targeting delivery system for tumor therapy.

Nutritional Intervention for the Treatment and Prevention Against Novel Coronavirus-19

Introduction:: The ongoing pandemic of Severe Acute Respiratory Syndrome coronavirus-2 (SARS COV-2) has jeopardized people’s health and the global economy. The infection caused by these viruses inflicts immunosuppression and an unprecedented range of symptoms leading to mortality. At this stage, there are no countermeasures or medicines to overcome rapid disease proliferation and aberrant immunological response. Objectives:: The study aims to determine different immunomodulatory therapeutics that could be potential agents to alleviate viral and other lethal infections and possibly rejuvenate immunological and tissue repair response against this disease. Methods:: A review of the literature was performed by screening different scientific databases to procure various immunomodulatory therapies for the treatment of SAR COV-2. Results:: A comprehensive literature review indicated that different foods rich in vitamins (A-D), selenium and iron can enhance immunological response against various deleterious infections, whereas different nutritious drinks that include hydrogen-enriched water and green tea alleviate inflammation and elicit wound healing properties. Black cumin seeds and Garlic have a myriad of biological activities due to abundant bioactive phytochemicals that play an important role in the elimination of various bacterial and viral infections. Conclusion:: These foods/supplements are relatively safe to consume and possess high toxicity profile and could be a potential nutritional intervention in order to create adequate immunity within a population to fight against this prevailing infection.

Total Phenolic Fraction (TPF) from Extra Virgin Olive Oil: Induction of apoptotic-like cell death in Leishmania spp. promastigotes and in vivo potential of therapeutic immunomodulation.

Leishmaniasis is a serious multifactorial parasitic disease with limited treatment options. Current chemotherapy is mainly consisted of drugs with serious drawbacks such as toxicity, variable efficacy and resistance. Alternative bioactive phytocompounds may provide a promising source for discovering new anti-leishmanial drugs. Extra Virgin Olive Oil (EVOO), a key-product in the Mediterranean diet, is rich in phenols which are associated with anti-inflammatory, anti-cancer and anti-microbial effects. In this study, we investigate the anti-leishmanial effect of Total Phenolic Fraction (TPF) derived from EVOO in both in vitro and in vivo systems by investigating the contributing mechanism of action. We tested the ability of TPF to cause apoptotic-like programmed cell death in L. infantum and L. major exponential-phase promastigotes by evaluating several apoptotic indices, such as reduction of proliferation rate, sub-G0/G1 phase cell cycle arrest, phosphatidylserine externalization, mitochondrial transmembrane potential disruption and increased ROS production, by using flow cytometry and microscopy techniques. Moreover, we assessed the therapeutic effect of TPF in L. major-infected BALB/c mice by determining skin lesions, parasite burden in popliteal lymph nodes, Leishmania-specific antibodies and biomarkers of tissue site cellular immune response, five weeks post-treatment termination. Our results show that TPF triggers cell-cycle arrest and apoptotic-like changes in Leishmania spp. promastigotes. Moreover, TPF treatment induces significant reduction of parasite burden in draining lymph nodes together with an antibody profile indicative of the polarization of Th1/Th2 immune balance towards the protective Th1-type response, characterized by the presence of IFN-γ-producing CD4+ T-cells and increased Tbx21/GATA-3 gene expression ratio in splenocytes. TPF exhibits chemotherapeutic anti-leishmanial activity by inducing programmed cell death on cell-free promastigotes and immunomodulatory properties that induce in vivo T cell-mediated responses towards the protective Th1 response in experimental cutaneous leishmaniasis. These findings enable deeper understanding of TPF's dual mode of action that encourages further studies.

Biological and physical approaches on the role of piplartine (piperlongumine) in cancer

Chronic inflammation provides a favorable microenvironment for tumorigenesis, which opens opportunities for targeting cancer development and progression. Piplartine (PL) is a biologically active alkaloid from long peppers that exhibits anti-inflammatory and antitumor activity. In the present study, we investigated the physical and chemical interactions of PL with anti-inflammatory compounds and their effects on cell proliferation and migration and on the gene expression of inflammatory mediators. Molecular docking data and physicochemical analysis suggested that PL shows potential interactions with a peptide of annexin A1 (ANXA1), an endogenous anti-inflammatory mediator with therapeutic potential in cancer. Treatment of neoplastic cells with PL alone or with annexin A1 mimic peptide reduced cell proliferation and viability and modulated the expression of MCP-1 chemokine, IL-8 cytokine and genes involved in inflammatory processes. The results also suggested an inhibitory effect of PL on tubulin expression. In addition, PL apparently had no influence on cell migration and invasion at the concentration tested. Considering the role of inflammation in the context of promoting tumor initiation, the present study shows the potential of piplartine as a therapeutic immunomodulator for cancer prevention and progression.

The Aryl Hydrocarbon Receptor in Asthma: Friend or Foe?

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that has emerged as an important player in asthma control. AhR is responsive to environmental molecules and endogenous or dietary metabolites and regulates innate and adaptive immune responses. Binding of this receptor by different ligands has led to seemingly opposite responses in different asthma models. In this review, we present two sides of the same coin, with the beneficial and deleterious roles of AhR evaluated using known endogenous or exogenous ligands, deficient mice or antagonists. On one hand, AhR has an anti-inflammatory role since its activation in dendritic cells blocks the generation of pro-inflammatory T cells or shifts macrophages toward an anti-inflammatory M2 phenotype. On the other hand, AhR activation by particle-associated polycyclic aromatic hydrocarbons from the environment is pro-inflammatory, inducing mucus hypersecretion, airway remodelling, dysregulation of antigen presenting cells and exacerbates asthma features. Data concerning the role of AhR in cells from asthmatic patients are also reviewed, since AhR could represent a potential target for therapeutic immunomodulation.

Development of the first reference antibody panel for qualification and validation of cytokine release assay platforms – Report of an international collaborative study

Immunomodulatory therapeutics such as monoclonal antibodies (mAb) carry an inherent risk of undesired immune reactions. One such risk is cytokine release syndrome (CRS), a rapid systemic inflammatory response characterized by the secretion of pro-inflammatory cytokines from immune cells. It is crucial for patient safety to correctly identify potential risk of CRS prior to first-in-human dose administration. For this purpose, a variety of in vitro cytokine release assays (CRA) are routinely used as part of the preclinical safety assessment of novel therapeutic mAbs. One of the challenges for the development and comparison of CRA performance is the lack of availability of standard positive and negative control mAbs for use in assay qualification. To address this issue, the National Institute for Biological Standards and Control (NIBSC) developed a reference panel of lyophilised mAbs known to induce CRS in the clinic: human anti-CD52, mouse anti-CD3 and human superagonistic (SA) anti-CD28 mAb manufactured according to the respective published sequences of Campath-1H® (alemtuzumab, IgG1) , Orthoclone OKT-3® (muromonab, IgG2a) and TGN1412 (theralizumab, IgG4), as well as three isotype matched negative controls (human IgG1, mouse IgG2a and human IgG4, respectively).The relative capacity of these control mAbs to stimulate the release of IFN-γ, IL-2, TNF-α and IL-6 in vitro was evaluated in eleven laboratories in an international collaborative study mediated through the HESI Immuno-safety Technical Committee Cytokine Release Assay Working Group. Participants tested the NIBSC mAbs in a variety of CRA platforms established at each institution. This paper presents the results from the centralised cytokine quantification on all the plasma/supernatants corresponding to the stimulation of immune cells in the different CRA platforms by a single concentration of each mAb. Each positive control mAb induced significant cytokine release in most of the tested CRA platforms. There was a high inter-laboratory variability in the levels of cytokines produced, but similar patterns of response were observed across laboratories that replicated the cytokine release patterns previously published for the respective clinical therapeutic mAbs. Therefore, the positive and negative mAbs are suitable as a reference panel for the qualification and validation of CRAs, comparison of different CRA platforms (e.g. solid vs aqueous phase), and intra- and inter-laboratory comparison of CRA performance. Thus, the use of this panel of positive and negative control mAbs will increase the confidence in the robustness of a CRA platform to identify a potential CRS risk for novel immunomodulatory therapeutic candidates.

Helminth Induced Immunoregulation and Novel Therapeutic Avenue of Allergy.

Allergic diseases are increasing at an alarming rate worldwide, particularly in developed countries. In contrast, there is a decrease in the prevalence of helminthic infections and other neglected diseases. The hygiene hypothesis elaborates parasitic infection, and allergy-associated diseases have an inverse relationship. Acute helminthic infection and allergic reaction stimulate Type 2 helper cells (Th2) immune response with up-regulation of cytokines IL-4-, IL-5-, and IL-13-mediated IgE and mast cell production, as well as eosinophilia. However, people who chronically suffer from helminthic infections are demarcated through polarized Th2 resulting in alternative macrophage activation and T regulatory response. This regulatory system reduces allergy incidence in individuals that are chronically diseased through helminth. As a result, the excretory-secretory (ES) substance derived from parasites and extracellular vesicular components can be used as a novel therapeutic modality of allergy. Therefore, the aim of this review meticulously explored the link between helminth infection and allergy, and utilization of the helminth secretome for therapeutic immunomodulation.

The discovery of potent small molecule activators of human STING.

The adaptor protein STING plays a major role in innate immune sensing of cytosolic nucleic acids, by triggering a robust interferon response. Despite the importance of this protein as a potential therapeutic target for serious unmet medical conditions including cancer and infectious disease there remains a paucity of STING ligands. Starting with a benzothiazinone series of weak STING activators (human EC50 ∼10μM) we identified several chemotypes with sub-micromolar STING activity across all the major protein polymorphs. An example compound 53 based on an oxindole core structure demonstrated robust on-target functional activation of STING (human EC50 185nM) in immortalised and primary cells and a cytokine induction fingerprint consistent with STING activation. Our study has identified several related series of potent small molecule human STING activators with potential to be developed as immunomodulatory therapeutics.

Lymph-directed nitric oxide increases immune cell access to lymph-borne nanoscale solutes

Lymph nodes (LNs) are immune organs housing high concentrations of lymphocytes, making them critical targets for therapeutic immunomodulation in a wide variety of diseases. While there is great interest in targeted drug delivery to LNs, many nanoscale drug delivery carriers have limited access to parenchymal resident immune cells compared to small molecules, limiting their efficacy. Nitric oxide (NO) is a potent regulator of vascular and lymphatic transport and a promising candidate for modulating nanocarrier access to LNs, but its lymphatic accumulation is limited by its low molecular weight and high reactivity. In this work, we employ S-nitrosated nanoparticles (SNO-NP), a lymphatic-targeted delivery system for controlled NO release, to investigate the effect of NO application on molecule accumulation and distribution within the LN. We evaluated the LN accumulation, spatial distribution, and cellular distribution of a panel of fluorescent tracers after intradermal administration alongside SNO-NP or a small molecule NO donor. While SNO-NP did not alter total tracer accumulation in draining lymph nodes (dLNs) or affect active cellular transport of large molecules from the injection site, its application enhanced the penetration of nanoscale 30 nm dextrans into the LN and their subsequent uptake by LN-resident lymphocytes, while nontargeted NO delivery did not. These results further extended to a peptide-conjugated NP drug delivery system, which showed enhanced uptake by B cells and dendritic cells when administered alongside SNO-NP. Together, these results highlight the utility of LN-targeted NO application for the enhancement of nanocarrier access to therapeutically relevant LN-resident immune cells, making NO a potentially useful tool for improving LN drug delivery and immune responses.

A Promising Strategy for Non-Arteritic Anterior Ischemic Optic Neuropathy: Intravitreal Mesenchymal Stem Cell Exosome.

Non-arteritic anterior ischemic optic neuropathy (NAION) is a leading cause of optic nerverelated permanent visual impairment among individuals of over 50 years of age after glaucoma. Due to perplexing disorder regarding its pathogenesis, there is still no widely accepted and established treatment plan. Mesenchymal stem cells (MSCs) are one of the rare stem cell types that therapeutic agents for immunomodulation and ischemic tissue repair in clinical practice. However, there are certain disadvantages in using MSCs, such as potential tumorigenicity, need for autologous collection, and short survival time. Previous evidence suggested that MSC-exosome significantly attenuated post-ischemic neuronal damage and induced long-term neuroprotection associated with enhanced angiogenesis in MSCs. Therefore, we hypothesized that the intravitreal administration of MSC-exosome could be a potentially effective therapeutic approach for NAION by using a similar mechanism via promoting angiogenesis, neuro-regeneration, and neurological recovery, suppressing oxidative stress and reducing apoptosis, and suppressing inflammation and immunity based on its biological structure and function in NAION. Questions that need to be answered before testing clinically include dose regimen, injection frequency, the optimal duration of treatment, and duration of medication.

Abstract 4451: Combination of local mRNA immunotherapy with systemic immune checkpoint blockade demonstrates anti-tumor activity across a diverse range of preclinical syngeneic tumor models

Abstract Cancer immunotherapies with anti-PD-1/PD-L1 checkpoint blockade antibodies have revolutionized the treatment of a wide variety of malignancies. However, immunotherapy is ineffective in a significant subset of patients, or eventually results in the development of resistance with relapsed disease. Therefore, the future of immuno-oncology is identification of new agents that can be combined to increase the depth and breadth of anti-PD-1/PD-L1 therapies. Local intratumoral delivery of messenger RNA (mRNA)-based immunotherapies provides an opportunity to stimulate innate and adaptive immune responses against tumors and modulate tumor microenvironment, while limiting the side-effects related to systemic administration of immuno-modulatory therapeutics. We examined the local immunotherapy of synthetic mRNAs encoding immunomodulatory cytokines (single chain interleukin-12 (IL-12), interferon alpha (IFN-α), granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-15 sushi(IL-15)) alone and in combination with anti-PD-1 antibodies across 12 syngeneic mouse tumor models representing a diverse range of murine tumor types. Single agent treatment with cytokine mRNAs resulted in a significant anti-tumor response in 8 out of 12 tumor models. Combining cytokine mRNA with systemic anti-PD-1 immunotherapy further improved the anti-tumor response and resulted in tumor growth inhibition in two additional models otherwise unresponsive to single agent treatments. Transcriptome and cytokine analyses have been performed to understand factors which determine sensitivity to single agent and combination treatments with cytokine mRNA and anti-PD-1 antibodies. In summary, the combination of local cytokine mRNA immunotherapy with immune checkpoint blockade demonstrated improvement in the anti-tumor activity in a range of preclinical cancer models representing different murine tumor types. Based on these and other data, clinical testing of cytokine encoding mRNA mixture has recently been initiated (NCT03871348). Citation Format: Natalia V. Malkova, Tatiana Tolstykh, Mikhail Levit, Joachim Theilhaber, Andrew Hebert, Kevin Atchison, Adalis Maisonet, Christian Hotz, Ugur Sahin, Alexei Protopopov, Jack Pollard, Sukhvinder Sidhu, Dmitri Wiederschain, Timothy R. Wagenaar. Combination of local mRNA immunotherapy with systemic immune checkpoint blockade demonstrates anti-tumor activity across a diverse range of preclinical syngeneic tumor models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4451.

Nanomaterials as Smart Immunomodulator Delivery System for Enhanced Cancer Therapy.

Immunomodulatory therapeutics, which is conducive to overcoming tumor tolerance and restoring normal immune responses, has been proposed as a promising approach for enhanced cancer therapy and clinical advancement. However, issues including cytokine syndrome, inefficient delivery, hepatic dysfunction, and severe adverse reactions remain to be resolved. It is particularly critical to develop delivery technologies to overcome these limitations and further improve antitumor efficacy. With the continuous development of materials science, biomaterials have been widely used in the field of cancer treatment and have also provided exciting solutions to overcome the bottleneck of immunomodulatory therapeutics. A range of biomaterials, especially nanomaterials, has been developed as a local immunomodulatory platform to enhance targeted delivery, maintain drug stability, and reduce toxicity and side effects. In addition to single immunomodulatory therapeutics, nanomaterials have been demonstrated to possess significant potential in immunomodulatory therapeutics-based synergistic therapies, especially in combination with phototherapy, radiotherapy, chemotherapy, and immune checkpoint blockade. In this review, as background to the discussion of immunomodulatory therapeutics, we first described the mechanisms of action of multiple immunomodulators and discussed their current targeting agents. On this basis, we highlighted the latest advances in the use of nanomaterials-assisted immunomodulatory therapeutics and combination therapy to enhance anticancer immunity. In addition, current challenges and further promises for immunomodulatory therapeutics were also presented.

To inhibit TrxR1 is to inactivate STAT3–Inhibition of TrxR1 enzymatic function by STAT3 small molecule inhibitors

The transcription factor STAT3 plays a key role in cancer and immunity, being widely explored as a potential drug target for the development of novel immunomodulatory or anticancer therapeutics. The mechanisms of small molecule-derived inhibition of STAT3 appear, however, to be more complex than initially perceived. Our recent discovery, that some novel STAT3 inhibitors were bona fide inhibitors of the cytosolic selenoprotein oxidoreductase TrxR1 (TXNRD1), led us to explore the effects of a wide array of previously described STAT3 inhibitors on TrxR1 function. We found that 17 out of 23 tested STAT3 small molecule inhibitors indeed inhibited purified TrxR1 at the reported concentrations yielding STAT3 inhibition. All tested compounds were electrophilic as shown by direct reactivities with GSH, and several were found to also be redox cycling substrates of TrxR1. Ten compounds previously shown to inhibit STAT3 were here found to irreversibly inhibit cellular TrxR1 activity (Auranofin, Stattic, 5,15-DPP, Galiellalactone, LLL12, Napabucasin, BP1-102, STA-21, S3I-201 and Degrasyn (WP1130)). Our findings suggest that targeting of TrxR1 may be a common feature for many small molecules that inhibit cellular STAT3 function. It is possible that prevention of STAT3 activation in cells by several small molecules classified as STAT3 inhibitors can be a downstream event following TrxR1 inhibition. Therefore, the relationship between TrxR1 and STAT3 should be considered when studying inhibition of either of these promising drug targets.

Association Between Atopic Eczema and Cancer in England and Denmark

Associations between atopic eczema and cancer are unclear, with competing theories that increased immune surveillance decreases cancer risk and that immune stimulation increases cancer risk. Establishing baseline cancer risk in people with atopic eczema is important before exploring the association between new biologic drugs for atopic eczema and cancer risk. To investigate whether atopic eczema is associated with cancer. Matched cohort studies were conducted from January 2, 1998, to March 31, 2016, in England and from January 1, 1982, to June 30, 2016, in Denmark. We conducted our analyses between July 2018 and July 2019. The setting was English primary care and nationwide Danish data. Participants with atopic eczema (adults only in England and any age in Denmark) were matched on age, sex, and calendar period (as well as primary care practice in England only) to those without atopic eczema. Atopic eczema. Overall cancer risk and risk of specific cancers were compared in people with and without atopic eczema. In England, matched cohorts included 471 970 individuals with atopic eczema (median [IQR] age, 41.1 [24.9-60.7] years; 276 510 [58.6%] female) and 2 239 775 individuals without atopic eczema (median [IQR] age, 39.8 [25.9-58.4] years; 1 301 074 [58.1%] female). In Denmark, matched cohorts included 44 945 individuals with atopic eczema (median [IQR] age, 13.7 [1.7-21.1] years; 22 826 [50.8%] female) and 445 673 individuals without atopic eczema (median [IQR] age, 13.5 [1.7-20.8] years; 226 323 [50.8%] female). Little evidence was found of associations between atopic eczema and overall cancer (adjusted hazard ratio [HR], 1.04; 99% CI, 1.02-1.06 in England and 1.05; 99% CI, 0.95-1.16 in Denmark) or for most specific cancers. However, noncutaneous lymphoma risk was increased in people with atopic eczema in England (adjusted HR, 1.19; 99% CI, 1.07-1.34 for non-Hodgkin lymphoma [NHL] and 1.48; 99% CI, 1.07-2.04 for Hodgkin lymphoma). Lymphoma risk was increased in people with greater eczema severity vs those without atopic eczema (NHL adjusted HR, 1.06; 99% CI, 0.90-1.25 for mild eczema; 1.24; 99% CI, 1.04-1.48 for moderate eczema; and 2.08; 99% CI, 1.42-3.04 for severe eczema). Danish point estimates also showed increased lymphoma risk in people with moderate to severe eczema compared with those without atopic eczema (minimally adjusted HR, 1.31; 99% CI, 0.76-2.26 for NHL and 1.35; 99% CI, 0.65-2.82 for Hodgkin lymphoma), but the 99% CIs were wide. The findings from 2 large population-based studies performed in different settings do not support associations between atopic eczema and most cancers. However, an association was observed between atopic eczema and lymphoma, particularly NHL, that increased with eczema severity. This finding warrants further study as new immunomodulatory systemic therapeutics are brought to market that may alter cancer risk.

Early Rise in CRP is Associated with Progression to Respiratory Failure and Intubation in COVID-19 Patients

During the course of hospitalization, it is often unclear which COVID-19 patients will progress from non-critical to critical illness. Predicting disease trajectory is crucial for resource allocation and therapeutic intervention. In our single-center retrospective cohort analysis of the first 66 patients admitted for COVID-19 infection, we examined biomarkers of inflammation to distinguish non-critically ill inpatients who remained stable from those that had progressive respiratory failure requiring intubation and ICU transfer. Unlike the typical approach where patients are grouped into the two categories of non-critical and critical illness, COVID-19 patients in our study were classified into three cohorts by severity and stability of respiratory failure: stable non-critical illness (“mild”, 38 [58%]); non-critical illness at admission that progressed to critical illness (“progressive”, 21 [32%]); and critical illness at admission (“severe”, 7 [11%]). We found that while CRP level at admission was weakly associated with future progressive respiratory failure and appeared to have limited clinical utility. The progressive cohort showed modestly increased levels of CRP compared to the mild cohort, with significant overlap (125.0 ± 74 vs. 81.3 ± 57 mg/L, P = 0.05). Despite the limited predictive value of admission CRP levels, these measurements were indeed clinically relevant as they correlated with SOFA score (ρ = 0.41, P aO2/FiO2, r = -0.58, P P = 0.03; 48-72h post-admission: 185.0 ± 92 vs. 81.6 ± 63 mg/L, P = 0.002). Trends of inflammatory biomarkers, rather than absolute value at admission, may have most value for clinical triage and targeting therapeutic immunomodulation. Further, COVID-19 patients that are aggregated as “critically ill” in cross-sectional studies could represent two distinct inflammatory biomarker profiles and clinical presentations ( i.e., progressive versus severe cohorts).Funding: This work was supported by the American Heart Association Award 2014D007100 (E.Y.K.) and NIAMS T32 AR007530-35 (A.A.M.).Conflict of Interest: The authors declare no competing interests.Ethical Approval: This investigation was approved by the Partners Healthcare Institutional Review Board (Protocol 2014D007100). Opt-out consent was designated for the study.

IL-22 Plays a Critical Role in Maintaining Epithelial Integrity During Pulmonary Infection.

Pulmonary infection is a leading cause of hospitalization in world. Lung damage due to infection and host mediated pathology can have life threatening consequences. Factors that limit lung injury and/or promote epithelial barrier function and repair are highly desirable as immunomodulatory therapeutics. Over the last decade, interleukin−22 has been shown to have pulmonary epithelial protective functions at the mucosal immune interface with bacterial and viral pathogens. This article summarizes recent findings in this area and provides perspective regarding the role of IL-22 in mucosal host defense.

Curative efficacy of purified serine protease inhibitor PTF3 from potato tuber in experimental visceral leishmaniasis

To overcome the drug toxicity and frequent resistance of parasites against the conventional drugs for the healing of human visceral leishmaniasis, innovative plant derived antileishmanial components are very imperative. Fuelled by the complications of clinically available antileishmanial drugs, a novel potato serine protease inhibitor was identified with its efficacy on experimental visceral leishmaniasis (VL). The serine protease inhibitors from potato tuber extract (PTEx) bearing molecular mass of 39 kDa (PTF1), 23 kDa (PTF2) and 17 kDa (PTF3) were purified and identified. Among them, PTF3 was selected as the most active inhibitor (IC50 143.5 ± 2.4 µg/ml) regarding its antileishmanial property. Again, intracellular amastigote load was reduced upto 83.1 ± 1.7% in pre-treated parasite and 88.5 ± 0.5% in in vivo model with effective dose of PTF3. Protective immune response by PTF3 was noted with increased production of antimicrobial substances and up-regulation of pro-inflammatory cytokines. Therapeutic potency of PTF3 is also followed by 80% survival in infected hamster. The peptide mass fingerprint (MALDI-TOF) results showed similarity of PTF3 with serine protease inhibitors database. Altogether, these results strongly propose the effectiveness of PTF3 as potent immunomodulatory therapeutics for controlling VL.

The Network of Colonic Host Defense Peptides as an Innate Immune Defense Against Enteropathogenic Bacteria

Host defense peptides, abundantly secreted by colonic epithelial cells and leukocytes, are proposed to be critical components of an innate immune response in the colon against enteropathogenic bacteria, including Shigella spp., Salmonella spp., Clostridium difficile, and attaching and effacing Escherichia coli and Citrobacter rodentium. These short cationic peptides are bactericidal against both Gram-positive and -negative enteric pathogens, but may also exert killing effects on intestinal luminal microbiota. Simultaneously, these peptides modulate numerous cellular responses crucial for gut defenses, including leukocyte chemotaxis and migration, wound healing, cytokine production, cell proliferation, and pathogen sensing. This review discusses recent advances in our understanding of expression, mechanisms of action and microbicidal and immunomodulatory functions of major colonic host defense peptides, namely cathelicidins, β-defensins, and members of the Regenerating islet-derived protein III (RegIII) and Resistin-like molecule (RELM) families. In a theoretical framework where these peptides work synergistically, aspects of pathogenesis of infectious colitis reviewed herein uncover roles of host defense peptides aimed to promote epithelial defenses and prevent pathogen colonization, mediated through a combination of direct antimicrobial function and fine-tuning of host immune response and inflammation. This interactive host defense peptide network may decode how the intestinal immune system functions to quickly clear infections, restore homeostasis and avoid damaging inflammation associated with pathogen persistence during infectious colitis. This information is of interest in development of host defense peptides (either alone or in combination with reduced doses of antibiotics) as antimicrobial and immunomodulatory therapeutics for controlling infectious colitis.

Mesenchymal Stem/Stromal Cell-Derived Exosomes for Immunomodulatory Therapeutics and Skin Regeneration.

Exosomes are nano-sized vesicles that serve as mediators for cell-to-cell communication. With their unique nucleic acids, proteins, and lipids cargo compositions that reflect the characteristics of producer cells, exosomes can be utilized as cell-free therapeutics. Among exosomes derived from various cellular origins, mesenchymal stem cell-derived exosomes (MSC-exosomes) have gained great attention due to their immunomodulatory and regenerative functions. Indeed, many studies have shown anti-inflammatory, anti-aging and wound healing effects of MSC-exosomes in various in vitro and in vivo models. In addition, recent advances in the field of exosome biology have enabled development of specific guidelines and quality control methods, which will ultimately lead to clinical application of exosomes. This review highlights recent studies that investigate therapeutic potential of MSC-exosomes and relevant mode of actions for skin diseases, as well as quality control measures required for development of exosome-derived therapeutics.

Health benefits of carotenoids and potential application in poultry industry: A review.

Carotenoids are one of the widespread and ubiquitous lipid-soluble pigments that produce a wide range of colours which are universally found in various plants, microalgae, bacteria and fungi. Recently, interest in using carotenoids as feed ingredients has increased markedly owing to their bioactive and health-promoting properties. In terms of applications, carotenoid-rich products are widely available in the form of food and feed additive, supplements and natural colourants. Carotenoids play a versatile biological role that contributes to therapeutic effects, including anticancer, immunomodulators, anti-inflammatory, antibacterial, antidiabetic and neuroprotective. Dietary supplementation of carotenoids not only improves the production performance and health of poultry birds, but also enhances the quality of egg and meat. Several studies have suggested that the supplementation of plant derived carotenoids revealed numerous health-promoting activities in poultry birds. Carotenoids reduce the oxidative stress in pre-hatched and post-hatched birds through different mechanisms, including quench free radicals, activating antioxidant enzymes and inhibiting the signalling pathways. Use of carotenoids in poultry feed as a part of nutrient that confers bird health and improve product quality. Carotenoids play a critical role for the pigmentation of egg yolk, skin, legs, beak, comb, feather and fat. Birds consumed carotenoid deficient diet resulting hues of their egg yolk or pale coloured skin. Therefore, uniform pigmentation generally indicates the health status and quality of the poultry products. This review aims to gather recent information regarding bioactive properties of carotenoids and highlight pharmaceutical and health beneficial effects of carotenoids for the poultry industry. Additionally, it explores the importance of carotenoids as alternative feed ingredients for poultry to boost the production performance and replace synthetic medicine and nutrients.