Multi-functional nanomedicines for combinational cancer immunotherapy that transform cold tumors to hot tumors.

INTRODUCTION: Currently, cancer immunotherapy is widely used as a groundbreaking method that can completely cure advanced cancers. However, this new immunotherapy has the challenge of low patient response, which is often due to many patients' tumors having an immunosuppressive environment, known as cold tumors. AREAS COVERED: This review aims to introduce various nanomedicine-derived combinational cancer immunotherapy that can transform cold tumor into hot tumors. Initially, we discuss new technologies for combinational immunotherapy based on multifunctional nanomedicines that can deliver combinational immunogenic cell death (ICD) inducers, immune checkpoint blockades (ICBs) and immune modulators (IMs) to targeted tumor tissues at the same time. Ultimately, we highlight how multifunctional nanomedicines for combinational cancer immunotherapy can be used to transform cold tumor into hot tumors against advanced cancers. EXPERT OPINION: Nanomedicine-derived combinational cancer immunotherapy for delivering multiple ICD inducers, ICBs, and IMs at the same time is recognized as a new potential technology that can activate tumor immunity and simultaneously increase the therapeutic efficacy of immune cells that can transform effectively the cold tumors into hot tumors. Finally, nanomedicine-derived combinational cancer immunotherapy can solve the serious problems of low therapeutic efficacy that occurs when treating single drug or simple combinational drugs in cancer immunotherapy.

[Evaluation of the effectiveness of various regimens of the immunomodulatory drug Superlimf in the prevention of relapses of chronic abacterial prostatitis].

INTRODUCTION: Immune defense mechanisms, including a decrease in the functional activity of monocytes/macrophages, neutrophils, as well as a violation of the balance of pro- and anti-inflammatory cytokines, are important in the development of chronic abacterial prostatitis (CAP). The discovery of the cytokine system and the determination of their biological role in the development and functioning of the immune system and in the pathogenesis of a wide range of human diseases led to the development of a new direction in immunotherapy - cytokine therapy. The aim of the study was to evaluate the effectiveness of various regimens of the use of the immunomodulatory drug Superlimf in the prevention of recurrence of CAP. MATERIALS AND METHODS: The study included 90 patients with category IIIa CAP (NIH, 1995). All patients underwent basic complex therapy was performed, which included behavioral therapy, taking an 1-adrenoblocker, an antibacterial drug from the fluoroquinolone group for 28 days, as well as the drug Superlimph 10 ME 1 suppository rectally 2 times a day for 20 days. Dynamic follow-up was recommended for patients of group (CG) in the next 12 months. In the main group 1 (MG1), patients underwent basic complex therapy, after which a preventive courses of Superlimph 10 ME 1 suppository 1 time per day for 10 days every three months for 12 months was prescribed. In the main group 2 (MG2), patients also underwent basic complex therapy, after which a preventive courses of Superlimph 10 ME of 1 suppository was prescribed 2 times a day for 10 days every three months for 12 months. The effectiveness of the treatment was evaluated after 4 weeks (visit 2). Long-term treatment results were assessed after 3 months (visit 3), 6 months (visit 4), and 12 months (visit 5). RESULTS: The study groups were homogeneous, and the results of examinations obtained before treatment did not differ statistically significantly (p>0.05). At visit 2, 4 weeks after the start of therapy, a statistically significant positive dynamics of the studied indicators in the main groups and CG was recorded. Thus, the average score on the IPSS scale decreased by 56.4% from the initial value, on the Qol scale - by 57.7%, on the NIH-CPSI scale - 70.2%. The number of leukocytes in the prostate secretion decreased to the normal level to 7.9 in the field of vision, which is 86.2% less than the initial value. The average Qmax value also increased to a normal value of 15.2ml/s, which is 51.3% higher than the initial value (p<0.001). In this study, for the first time, a comparative analysis of two different regimens of preventive administration of the drug Superlimf was carried out. In MG1, the drug was prescribed to patients at a dose of 10 ME 1 time a day, in MG2 - 10 ME 2 times a day. The data obtained indicate a comparable effectiveness of both dosage regimens after 3 months of therapy. However, after 6 months and 12 months, the results in MG2 were statistically significantly better than in MG1. In addition, during 12 months of therapy, the number of relapses in MG2 was 2.3 times less. According to ultrasound examination, the volume of the prostate gland in CG, after a significant (p<0.001) decrease against the background of basic complex therapy, increased by 24.6% from visit 2 to visit 5, whereas in MG2 the average value of this indicator did not significantly change. And according to the Doppler study, by the end of the observation period at visit 5, hemodynamic parameters in CG were statistically significantly worse than in MG1 and MG2. CONCLUSION: Thus, the use of Superlymph in patients with CAP as a preventive therapy every 3 months results to a longer preservation of the therapeutic effect and improved hemodynamics in the prostate. In addition, preventive courses of Superlymph 10 units 2 times a day for 10 days led to an increase in the duration of the relapse-free period and a decrease in the number of recurrences within 12 months by 7 times, while preventive courses of Superlymph 10 units 1 time per day for 10 days decreased risk of recurrence by 3 times. According to our results, the most effective preventive scheme in patients with CAP is the use of Superlymph 10 units, 1 suppository 2 times a day for 10 days every 3 months.

Discontinuation of disease-modifying therapy in MS patients over 60 years old and its impact on relapse rate and disease progression.

BACKGROUND / AIMS: The benefit of disease-modifying therapy (DMT) is unclear for older patients with multiple sclerosis (MS), namely those who have not experienced clinical disease activity for a prolonged time. We aimed to compare baseline differences and clinical outcomes between DMT discontinuers and continuers in a cohort of MS patients older than 60 years. METHODS: Retrospective, observational study identifying MS patients aged over 60 years, stable on DMT> 24 months. Additional inclusion criteria were a previous diagnosis of relapsing MS and a minimum follow-up period of 24 months. Differences between groups (continuers/discontinuers) were assessed. For risk of relapse and of confirmed disability worsening at follow up, a time to outcome survival model was constructed using Cox proportional hazards regression, testing for possible risk predictors. RESULTS: Thirty-five patients were included (68.6% female), with a mean age at diagnosis of 42.1 ( ± 9.5) years and a median EDSS score of 3 (IQR 2) at the age of 60 years (baseline). Thirteen patients discontinued DMT after baseline, in a mean follow-up time of 77.1 months ( ± 40.2). No differences were found between DMT continuers vs discontinuers. DMT discontinuation did not predict risk to relapse (HR 0.38, 95%CI 0.04-3.80, p = 0.408) or disability worsening at follow-up (HR 0.83, 95%CI 0.31-2.22, p = 0.712). MRI gadolinium-enhancing lesions and EDSS score > 3 at baseline were found to be independent predictors of risk to relapse and disability worsening at follow-up, respectively. CONCLUSION: DMT discontinuation did not seem to influence clinical outcome, equating with the perceived limited effect of continued immunomodulation on older stable and/or progressive patients.

The vital role of animal, marine, and microbial natural products against COVID-19.

CONTEXT: Since the outbreak of SARS-CoV-2, researchers have been working on finding ways to prevent viral entry and pathogenesis. Drug development from naturally-sourced pharmacological constituents may be a fruitful approach to COVID-19 therapy. OBJECTIVE: Most of the published literature has focussed on medicinal plants, while less attention has been given to biodiverse sources such as animal, marine, and microbial products. This review focuses on highlighting natural products and their derivatives that have been evaluated for antiviral, anti-inflammatory, and immunomodulatory properties. METHODS: We searched electronic databases such as PubMed, Scopus, Science Direct and Springer Link to gather raw data from publications up to March 2021, using terms such as 'natural products', marine, micro-organism, and animal, COVID-19. We extracted a number of documented clinical trials of products that were tested in silico, in vitro, and in vivo which paid specific attention to chemical profiles and mechanisms of action. RESULTS: Various classes of flavonoids, 2 polyphenols, peptides and tannins were found, which exhibit inhibitory properties against viral and host proteins, including 3CLpro, PLpro, S, hACE2, and NF-κB, many of which are in different phases of clinical trials. DISCUSSION AND CONCLUSIONS: The synergistic effects of logical combinations with different mechanisms of action emphasizes their value in COVID19 management, such as iota carrageenan nasal spray, ermectin oral drops, omega-3 supplementation, and a quadruple treatment of zinc, quercetin, bromelain, and vitamin C. Though in vivo efficacy of these compounds has yet to be established, these bioproducts are potentially useful in counteracting the effects of SARS-CoV-2.

Impact of intravesical instillation of a novel biological response modifier (P-MAPA) on progress of non-muscle invasive bladder cancer treatment in a rat model.

This work describes the effects of immunotherapy with Protein Aggregate Magnesium-Ammonium Phospholinoleate-Palmitoleate Anhydride in the treatment of non-muscle invasive bladder cancer in an animal model. NMIBC was induced by treating female Fischer 344 rats with N-methyl-N-nitrosourea. After treatment with MNU, the rats were distributed into four experimental groups: Control (without MNU) group, MNU (cancer) group, MNU-BCG (Bacillus Calmette-Guerin) group, and MNU-P-MAPA group. P-MAPA intravesical treatment was more effective in histopathological recovery from cancer state in relation to BCG treatment. Western blot assays showed an increase in the protein levels of c-Myc, COUP-TFII, and wild-type p53 in P-MAPA-treated rats in relation to BCG-treated rats. In addition, rats treated with P-MAPA intravesical immunotherapy showed the highest BAX protein levels and the lowest proliferation/apoptotic ratio in relation to BCG-treated rats, pointing out a preponderance of apoptosis. P-MAPA intravesical treatment increased the wild-type p53 levels and enhanced c-Myc/COUP-TFII-induced apoptosis mediated by p53. These alterations were fundamental for histopathological recovery from cancer and for suppress abnormal cell proliferation. This action of P-MAPA on apoptotic pathways may represent a new strategy for treating NMIBC.

Immune interventions in COVID-19: a matter of time?

As the COVID-19 pandemic is still ongoing, and considering the lack of efficacy of antiviral strategies to this date, and the reactive hyperinflammation leading to tissue lesions and pneumonia, effective treatments targeting the dysregulated immune response are more than ever required. Immunomodulatory and immunosuppressive drugs have been repurposed in severe COVID-19 with contrasting results. The heterogeneity in the timing of treatments administrations could be accountable for these discrepancies. Indeed, many studies included patients at different timepoints of infection, potentially hiding the beneficial effects of a time-adapted intervention. We aim to review the available data on the kinetics of the immune response in beta-coronaviruses infections, from animal models and longitudinal human studies, and propose a four-step model of severe COVID-19 timeline. Then, we discuss the results of the clinical trials of immune interventions with regards to the timing of administration, and finally suggest a time frame in order to delineate the best timepoint for each treatment.

A Helminth-Derived Chitinase Structurally Similar to Mammalian Chitinase Displays Immunomodulatory Properties in Inflammatory Lung Disease.

Immunomodulation of airway hyperreactivity by excretory-secretory (ES) products of the first larval stage (L1) of the gastrointestinal nematode Trichuris suis is reported by us and others. Here, we aimed to identify the proteins accounting for the modulatory effects of the T. suis L1 ES proteins and studied six selected T. suis L1 proteins for their immunomodulatory efficacy in a murine OVA-induced allergic airway disease model. In particular, an enzymatically active T. suis chitinase mediated amelioration of clinical signs of airway hyperreactivity, primarily associated with suppression of eosinophil recruitment into the lung, the associated chemokines, and increased numbers of RELMα + interstitial lung macrophages. While there is no indication of T. suis chitinase directly interfering with dendritic cell activation or antigen presentation to CD4 T cells, treatment of allergic mice with the worm chitinase influenced the hosts' own chitinase activity in the inflamed lung. The three-dimensional structure of the T. suis chitinase as determined by high-resolution X-ray crystallography revealed high similarities to mouse acidic mammalian chitinase (AMCase) but a unique ability of T. suis chitinase to form dimers. Our data indicate that the structural similarities between the parasite and host chitinase contribute to the disease-ameliorating effect of the helminth-derived chitinase on allergic lung inflammation.

Dietary Supplementation with Biobran/MGN-3 Increases Innate Resistance and Reduces the Incidence of Influenza-like Illnesses in Elderly Subjects: A Randomized, Double-Blind, Placebo-Controlled Pilot Clinical Trial.

Influenza-like illness (ILI) remains a major cause of severe mortality and morbidity in the elderly. Aging is associated with a decreased ability to sense pathogens and mount effective innate and adaptive immune responses, thus mandating the development of protective nutraceuticals. Biobran/MGN-3, an arabinoxylan from rice bran, has potent anti-aging and immunomodulatory effects, suggesting that it may be effective against ILI. The objective of the current study was to investigate the effect of Biobran/MGN-3 on ILI incidence, natural killer (NK) cell activity, and the expressions of RIG-1 (retinoic acid-inducible gene 1), MDA5 (melanoma differentiation-associated protein 5), and their downstream signaling genes ISG-15 (interferon-stimulated genes 15) and MX1 (myxovirus (influenza) resistance 1, interferon-inducible). A double-blind, placebo-controlled clinical trial included eighty healthy older adults over 55 years old, 40 males and 40 females, who received either a placebo or Biobran/MGN-3 (500 mg/day) for 3 months during known ILI seasonality (peak incidence) in Egypt. The incidence of ILI was confirmed clinically according to the WHO case definition criteria. Hematological, hepatic, and renal parameters were assessed in all subjects, while the activity of NK and NKT (natural killer T) cells was assessed in six randomly chosen subjects in each group by the degranulation assay. The effect of Biobran/MGN-3 on RIG-1 and MDA5, as well as downstream ISG15 and MX1, was assessed in BEAS-2B pulmonary epithelial cells using flow cytometry. The incidence rate and incidence density of ILI in the Biobran/MGN-3 group were 5.0% and 0.57 cases per 1000 person-days, respectively, compared to 22.5% and 2.95 cases per 1000 person-days in the placebo group. Furthermore, Biobran/MGN-3 ingestion significantly enhanced NK activity compared to the basal levels and to the placebo group. In addition, Biobran/MGN-3 significantly upregulated the expression levels of RIG-1, MDA5, ISG15, and MX1 in the human pulmonary epithelial BEAS-2B cell lines. No side effects were observed. Taken together, Biobran/MGN-3 supplementation enhanced the innate immune response of elderly subjects by upregulating the NK activity associated with reduction of ILI incidence. It also upregulated the intracellular RIG-1, MDA5, ISG15, and MX1 expression in pulmonary epithelial tissue cultures. Biobran/MGN-3 could be a novel agent with prophylactic effects against a wide spectrum of respiratory viral infections that warrants further investigation.

Inflammatory myopathies: shedding light on promising agents and combination therapies in clinical trials.

INTRODUCTION: Due to new insights into the pathogenesis of inflammatory myopathies - in short myositis - and the urgent need for new treatment options in patients who are refractory to standard therapy, multiple novel drugs have been developed and studied in clinical trials. In light of this exciting development, a critical evaluation of the present data is necessary in order to identify the best pathway to future treatment of inflammatory myopathies. AREAS COVERED: This review focuses on the current evidence from clinical trials in myositis and encompasses dermatomyositis, polymyositis, necrotizing myopathy, antisynthetase-syndrome, overlap myositis, and inclusion body myositis. The results of studies on new therapeutic agents are summarized, in particular larger cohort studies and randomized trials from recent years. When such data were not available, earlier and smaller representative studies were included instead. EXPERT OPINION: Current studies in most myositis subtypes have shown positive effects of novel biologicals such as abatacept, sifalimumab, JAK-Inhibitors as well as known agents such as rituximab, but further studies are needed to confirm these observations. In inclusion body myositis, the eagerly awaited recent therapeutic trials have missed their primary endpoints, except for the phase 2 study with rapamycin, which has demonstrated significant improvements in secondary endpoints. Future trials will also need to focus on combination therapies of multiple immunomodulatory agents.

Discovery of BPR1R024, an Orally Active and Selective CSF1R Inhibitor that Exhibits Antitumor and Immunomodulatory Activity in a Murine Colon Tumor Model.

Colony-stimulating factor-1 receptor (CSF1R) is implicated in tumor-associated macrophage (TAM) repolarization and has emerged as a promising target for cancer immunotherapy. Herein, we describe the discovery of orally active and selective CSF1R inhibitors by property-driven optimization of BPR1K871 (9), our clinical multitargeting kinase inhibitor. Molecular docking revealed an additional nonclassical hydrogen-bonding (NCHB) interaction between the unique 7-aminoquinazoline scaffold and the CSF1R hinge region, contributing to CSF1R potency enhancement. Structural studies of CSF1R and Aurora kinase B (AURB) demonstrated the differences in their back pockets, which inspired the use of a chain extension strategy to diminish the AURA/B activities. A lead compound BPR1R024 (12) exhibited potent CSF1R activity (IC50 = 0.53 nM) and specifically inhibited protumor M2-like macrophage survival with a minimal effect on antitumor M1-like macrophage growth. In vivo, oral administration of 12 mesylate delayed the MC38 murine colon tumor growth and reversed the immunosuppressive tumor microenvironment with the increased M1/M2 ratio.

Comparative assessment of proliferation and immunomodulatory potential of Hypericum perforatum plant and callus extracts on mesenchymal stem cells derived adipose tissue from multiple sclerosis patients.

BACKGROUND: Mesenchymal stem cells-derived adipose tissue (AT-MSCs) are recognized for the treatment of inflammatory diseases including multiple sclerosis (MS). Hypericum perforatum (HP) is an anti-inflammatory pharmaceutical plant with bioactive compounds. Plant tissue culture is a technique to improve desired pharmacological potential. The aim of this study was to compare the anti-inflammatory and proliferative effects of callus with field-growing plant extracts of HP on AT-MSCs derived from MS patients. MATERIALS AND METHODS: AT-MSCs were isolated and characterized. HP callus was prepared and exposure to light spectrum (blue, red, blue-red, and control). Total phenols, flavonoids, and hypericin of HP callus and plant extracts were measured. The effects of HP extracts concentrations on proliferation were evaluated by MTT assay. Co-culture of AT-MSCs: PBMCs were challenged by HP plant and callus extracts, and Tregs percentage was assessed by flow cytometry. RESULTS: Identification of MSCs was performed. Data showed that blue light could stimulate total phenols, flavonoids, and hypericin. MTT test demonstrated that plant extract in concentrations (0.03, 1.2, 2.5 and 10 µg/ml) and HP callus extract in 10 µg/ml significantly increased. Both HP extracts lead to an increase in Tregs percentage in all concentrations. In particular, a comparison between HP plant and callus extracts revealed that Tregs enhanced 3-fold more than control groups in the concentration of 10 µg/ml callus. CONCLUSIONS: High concentrations of HP extracts showed effectiveness on AT-MSCs proliferation and immunomodulatory properties with a certain consequence in callus extract. HP extracts may be considered as supplementary treatments for the patients who receiving MSCs transplantation.

Early administration of MPC-n(IVIg) selectively accumulates in ischemic areas to protect inflammation-induced brain damage from ischemic stroke.

Ischemic stroke is an acute and severe neurological disease, which leads to disability and death. Immunomodulatory therapies exert multiple remarkable protective effects during ischemic stroke. However, patients suffering from ischemic stroke do not benefit from immunomodulatory therapies due to the presence of the blood-brain barrier (BBB) and their off-target effects. Methods: We presented a delivery strategy to optimize immunomodulatory therapies by facilitating BBB penetration and selectively delivering intravenous immunoglobulin (IVIg) to ischemic regions using 2-methacryloyloxyethyl phosphorylcholine (MPC)-nanocapsules, MPC-n(IVIg), synthesized using MPC monomers and ethylene glycol dimethyl acrylate (EGDMA) crosslinker via in situ polymerization. In vitro and in vivo experiments verify the effect and safety of MPC-n(IVIg). Results: MPC-n(IVIg) efficiently crosses the BBB and IVIg selectively accumulates in ischemic areas in a high-affinity choline transporter 1 (ChT1)-overexpression dependent manner via endothelial cells in ischemic areas. Moreover, earlier administration of MPC-n(IVIg) more efficiently deliver IVIg to ischemic areas. Furthermore, the early administration of low-dosage MPC-n(IVIg) decreases neurological deficits and mortality by suppressing stroke-induced inflammation in the middle cerebral artery occlusion model. Conclusion: Our findings indicate a promising strategy to efficiently deliver the therapeutics to the ischemic target brain tissue and lower the effective dose of therapeutic drugs for treating ischemic strokes.

Inflammatory Response to Spinal Cord Injury and Its Treatment.

Spinal cord injury (SCI), as one of the intractable diseases in clinical medicine, affects thousands of human beings, and the pathologic changes after injury have been a hot spot for exploration in clinical medicine. With the development of new treatments, the survival of patients has shown an increasing trend; however, the inflammatory response after injury has not yet been effectively controlled. SCI is divided into primary injury and secondary injury according to the time of injury and pathophysiologic changes. Primary injury occurs immediately and the damage to the injury site is irreversible; however, secondary injury occurs after primary injury and involves pathologic changes at the cellular and molecular levels, which are reversible. Thus, the inflammatory response from secondary injuries has become the main direction of research. In recent years, a complex pathophysiologic mechanism has gradually been unveiled, which has been followed by an upgrade of treatment methods. This article describes the mechanisms of the inflammatory response after SCI and the mainstream treatment modalities. Also, neuroprotective agents and nerve regeneration agent agents are commonly used in the treatment of SCI; the therapeutic mechanism and classification of these agents are reviewed.

Propolis increases Foxp3 expression and lymphocyte proliferation in HIV-infected people: A randomized, double blind, parallel-group and placebo-controlled study.

HIV infection and the prolonged use of antiretroviral therapy (ART) contribute to persistent inflammation and immune deregulation in people living with HIV/AIDS (PLWHA). Propolis is a bee product with plenty of biological properties, including immunomodulatory and anti-inflammatory action. This work aimed to evaluate possible changes in the immune/inflammatory response in PLWHA under ART after propolis intake. Asymptomatic PLWHA were double-blindly randomized into parallel groups receiving propolis (500 mg/day, n = 20) for 3 months or placebo (n = 20). Plasma cytokines (TNF-α, IL-2, IL-4, IL-6, IL-10 and IL17) were evaluated by cytometric bead array; cytokine production by PBMC (IFN-γ, IL-5, IL-17, IL-10, IL-1ß, IL-18, and IL-33) was assessed by ELISA; gene expression (T-bet, GATA-3, RORγt and Foxp3) was determined by RT-qPCR, and cell proliferation was analysed by flow cytometry using CFSE staining. The average of gender, age, CD4+/CD8+ T cell count, time of diagnosis and treatment were similar in both groups. No differences were observed in cytokine levels nor in inflammasome activation. However, Pearson's correlation showed that IL-10 was directly correlated to CD4+ T cell count and inversely to IFN-γ after treatment with propolis. Foxp3 expression and lymphocyte proliferation increased in the propolis group. Data suggested that daily propolis consumption may improve the immune response and decrease the inflammatory status in asymptomatic PLWHA under ART.

Nanotechnology-based immunotherapies to combat cancer metastasis.

Emerging concepts in nanotechnology have gained particular attention for their clinical translation of immunotherapies of cancer, autoimmune and infectious diseases. Several nanoconstructs have been engineered with unique structural, physicochemical, and functional features as robust alternatives for conventional chemotherapies. Traditional cancer therapies like chemotherapy, radiotherapy, and ultimately surgery are the most widely practiced in biomedical settings. Biomaterials and nanotechnology have introduced vehicles for drug delivery and have revolutionized the concept of the modern immunotherapeutic paradigm. Various types of nanomaterials, such as nanoparticles and, more specifically, drug-loaded nanoparticles are becoming famous for drug delivery applications because of safety, patient compliance, and smart action. Such therapeutic modalities have acknowledged regulatory endorsement and are being used in twenty-first-century clinical settings. Considering the emerging concepts and landscaping potentialities, herein, we spotlight and discuss nanoparticle-based immunotherapies as a smart and sophisticated drug delivery approach to combat cancer metastasis. The introductory part of this manuscript discusses a broad overview of cancer immunotherapy to understand better the tumor microenvironment and nanotechnology-oriented immunomodulatory strategies to cope with advanced-stage cancers. Following that, most addressable problems allied with conventional immunotherapies are given in comparison to nanoparticle-based immunotherapies. The later half of this work comprehensively highlights the requisite delivery of various bioactive entities with particular cases and examples. Finally, this review also encompasses a comprehensive concluding overview and future standpoints to strengthen a successful clinical translation of nanoparticle-based immunotherapies as a smart and sophisticated drug delivery approach.

The immunoenhancement effects of sea buckthorn pulp oil in cyclophosphamide-induced immunosuppressed mice.

In this study, the immunomodulatory effect of sea buckthorn (SBT) pulp oil was elucidated in immunosuppressed Balb/c mice induced by cyclophosphamide (CTX). The results showed that SBT pulp oil could reverse the decreasing trend of body weight, thymus/spleen index and hematological parameters induced by CTX. Compared with immunosuppressive mice induced by CTX, SBT pulp oil could enhance NK cytotoxicity, macrophage phagocytosis, and T lymphocyte proliferation, and regulate the proportion of T cell subsets in mesenteric lymph nodes (MLN), and promote the production of secretory immunoglobulin A (sIgA), IFN-γ, IL-2, IL-4, IL-12 and TNF-α in the intestines. In addition, SBT pulp oil can promote the production of short fatty acids (SCFAs), increase the diversity of gut microbiota, improve the composition of intestinal flora, increase the abundance of Alistipes, Bacteroides, Anaerotruncus, Lactobacillus, ASF356, and Roseburia, while decreasing the abundance of Mucispirillum, Anaeroplasma, Pelagibacterium, Brevundimonas, Ochrobactrum, Acinetobacter, Ruminiclostridium, Blautia, Ruminiclostridium, Oscillibacter, and Faecalibaculum. This study shows that SBT pulp oil can regulate the diversity and composition of intestinal microflora in CTX-induced immunosuppressive Balb/c mice, thus enhancing the intestinal mucosa and systemic immune response. The results can provide a basis for understanding the function of SBT pulp oil and its application as a new probiotic and immunomodulator.

IL-10-Dependent Amelioration of Chronic Inflammatory Disease by Microdose Subcutaneous Delivery of a Prototypic Immunoregulatory Small Molecule.

One of the interventional strategies to reestablish the immune effector/regulatory balance, that is typically altered in chronic inflammatory diseases (CID), is the reinforcement of endogenous immunomodulatory pathways as the one triggered by interleukin (IL)-10. In a recent work, we demonstrated that the subcutaneous (sc) administration of an IL-10/Treg-inducing small molecule-based formulation, using a repetitive microdose (REMID) treatment strategy to preferentially direct the effects to the regional immune system, delays the progression of atherosclerosis. Here we investigated whether the same approach using other IL-10-inducing small molecule, such as the safe, inexpensive, and widely available polyphenol curcumin, could induce a similar protective effect in two different CID models. We found that, in apolipoprotein E deficient mice, sc treatment with curcumin following the REMID strategy induced atheroprotection that was not consequence of its direct systemic lipid-modifying or antioxidant activity, but instead paralleled immunomodulatory effects, such as reduced proatherogenic IFNγ/TNFα-producing cells and increased atheroprotective FOXP3+ Tregs and IL-10-producing dendritic and B cells. Remarkably, when a similar strategy was used in the neuroinflammatory model of experimental autoimmune encephalomyelitis (EAE), significant clinical and histopathological protective effects were evidenced, and these were related to an improved effector/regulatory cytokine balance in restimulated splenocytes. The essential role of curcumin-induced IL-10 for neuroprotection was confirmed by the complete abrogation of the clinical effects in IL-10-deficient mice. Finally, the translational therapeutic prospection of this strategy was evidenced by the neuroprotection observed in mice starting the treatment one week after disease triggering. Collectively, results demonstrate the power of a simple natural IL-10-inducing small molecule to tackle chronic inflammation, when its classical systemic and direct pharmacological view is shifted towards the targeting of regional immune cells, in order to rationally harness its immunopharmacological potential. This shift implies that many well-known IL-10-inducing small molecules could be easily reformulated and repurposed to develop safe, innovative, and accessible immune-based interventions for CID.

Evolution of Toll-like receptor 7/8 agonist therapeutics and their delivery approaches: From antiviral formulations to vaccine adjuvants.

Imidazoquinoline derivatives (IMDs) and related compounds function as synthetic agonists of Toll-like receptors 7 and 8 (TLR7/8) and one is FDA approved for topical antiviral and skin cancer treatments. Nevertheless, these innate immune system-activating drugs have potentially much broader therapeutic utility; they have been pursued as antitumor immunomodulatory agents and more recently as candidate vaccine adjuvants for cancer and infectious disease. The broad expression profiles of TLR7/8, poor pharmacokinetic properties of IMDs, and toxicities associated with systemic administration, however, are formidable barriers to successful clinical translation. Herein, we review IMD formulations that have advanced to the clinic and discuss issues related to biodistribution and toxicity that have hampered the further development of these compounds. Recent strategies aimed at enhancing safety and efficacy, particularly through the use of bioconjugates and nanoparticle formulations that alter pharmacokinetics, biodistribution, and cellular targeting, are described. Finally, key aspects of the biology of TLR7 signaling, such as TLR7 tolerance, that may need to be considered in the development of new IMD therapeutics are discussed.

Use of Disease-Modifying Therapies in Pediatric Relapsing-Remitting Multiple Sclerosis in the United Kingdom.

OBJECTIVES: To compare the real-world effectiveness of newer disease-modifying therapies (DMTs) vs injectables in children with relapsing-remitting multiple sclerosis (RRMS). METHODS: In this retrospective, multicenter study, from the UK Childhood Inflammatory Demyelination Network, we identified children with RRMS receiving DMTs from January 2012 to December 2018. Clinical and paraclinical data were retrieved from the medical records. Annualized relapse rates (ARRs) before and on treatment, time to relapse, time to new MRI lesions, and change in Expanded Disability Status Scale (EDSS) score were calculated. RESULTS: Of 103 children treated with DMTs, followed up for 3.8 years, relapses on treatment were recorded in 53/89 (59.5%) on injectables vs 8/54 (15%) on newer DMTs. The ARR was reduced from 1.9 to 1.1 on injectables (p < 0.001) vs 1.6 to 0.3 on newer DMTs (p = 0.002). New MRI lesions occurred in 77/89 (86.5%) of patients on injectables vs 26/54 (47%) on newer DMTs (p = 0.0001). Children on newer DMTs showed longer time to relapse, time to switch treatment, and time to new radiologic activity than patients on injectables (log-rank p < 0.01). After adjustment for potential confounders, multivariable analysis showed that injectables were associated with 12-fold increased risk of clinical relapse (adjusted hazard ratio [HR] = 12.12, 95% CI = 1.64-89.87, p = 0.015) and a 2-fold increased risk of new radiologic activity (adjusted HR = 2.78, 95% CI = 1.08-7.13, p = 0.034) compared with newer DMTs. At 2 years from treatment initiation, 38/103 (37%) patients had MRI activity in the absence of clinical relapses. The EDSS score did not change during the follow-up, and only 2 patients had cognitive impairment. CONCLUSION: Newer DMTs were associated with a lower risk of clinical and radiologic relapses in patients compared with injectables. Our study adds weight to the argument for an imminent shift in practice toward the use of newer, more efficacious DMTs in the first instance. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that newer DMTs (oral or infusions) are superior to injectables (interferon beta/glatiramer acetate) in reducing both clinical relapses and radiologic activity in children with RRMS.

The effects of a novel inhibitor of tumor necrosis factor (TNF) alpha on prepulse inhibition and microglial activation in two distinct rodent models of schizophrenia.

Increased neuroinflammation has been shown in individuals diagnosed with schizophrenia (SCHZ). This study evaluated a novel immune modulator (PD2024) that targets the pro-inflammatory cytokine tumor necrosis factor-alpha (TNFα) to alleviate sensorimotor gating deficits and microglial activation employing two different rodent models of SCHZ. In Experiment 1, rats were neonatally treated with saline or the dopamine D2-like agonist quinpirole (NQ; 1 mg/kg) from postnatal day (P) 1-21 which produces increases of dopamine D2 receptor sensitivity throughout the animal's lifetime. In Experiment 2, rats were neonatally treated with saline or the immune system stimulant polyinosinic:polycytidylic acid (Poly I:C) from P5-7. Neonatal Poly I:C treatment mimics immune system activation associated with SCHZ. In both experiments, rats were raised to P30 and administered a control diet or a novel TNFα inhibitor PD2024 (10 mg/kg) in the diet from P30 until P67. At P45-46 and from P60-67, animals were behaviorally tested on auditory sensorimotor gating as measured through prepulse inhibition (PPI). NQ or Poly I:C treatment resulted in PPI deficits, and PD2024 treatment alleviated PPI deficits in both models. Results also revealed that increased hippocampal and prefrontal cortex microglial activation produced by neonatal Poly I:C was significantly reduced to control levels by PD2024. In addition, a separate group of animals neonatally treated with saline or Poly I:C from P5-7 demonstrated increased TNFα protein levels in the hippocampus but not prefrontal cortex, verifying increased TNFα in the brain produced by Poly I:C. Results from this study suggests that that brain TNFα is a viable pharmacological target to treat the neuroinflammation known to be associated with SCHZ.