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Biomolecules Aug 2020There is a growing consensus that the antioxidant and anti-inflammatory properties of melatonin are of great importance in preserving the body functions and homeostasis,... (Review)
Review
There is a growing consensus that the antioxidant and anti-inflammatory properties of melatonin are of great importance in preserving the body functions and homeostasis, with great impact in the peripartum period and adult life. Melatonin promotes adaptation through allostasis and stands out as an endogenous, dietary, and therapeutic molecule with important health benefits. The anti-inflammatory and antioxidant effects of melatonin are intertwined and are exerted throughout pregnancy and later during development and aging. Melatonin supplementation during pregnancy can reduce ischemia-induced oxidative damage in the fetal brain, increase offspring survival in inflammatory states, and reduce blood pressure in the adult offspring. In adulthood, disturbances in melatonin production negatively impact the progression of cardiovascular risk factors and promote cardiovascular and neurodegenerative diseases. The most studied cardiovascular effects of melatonin are linked to hypertension and myocardial ischemia/reperfusion injury, while the most promising ones are linked to regaining control of metabolic syndrome components. In addition, there might be an emerging role for melatonin as an adjuvant in treating coronavirus disease 2019 (COVID 19). The present review summarizes and comments on important data regarding the roles exerted by melatonin in homeostasis and oxidative stress and inflammation related pathologies.
Topics: Adjuvants, Pharmaceutic; Animals; Anti-Inflammatory Agents; Antioxidants; COVID-19; Coronavirus Infections; Homeostasis; Humans; Melatonin; Pandemics; Pneumonia, Viral
PubMed: 32825327
DOI: 10.3390/biom10091211 -
Frontiers in Immunology 2022Adjuvants are indispensable components of vaccines for stimulating optimal immune responses to non-replicating, inactivated and subunit antigens. Eliciting balanced... (Review)
Review
Adjuvants are indispensable components of vaccines for stimulating optimal immune responses to non-replicating, inactivated and subunit antigens. Eliciting balanced humoral and T cell-mediated immunity is paramount to defend against diseases caused by complex intracellular pathogens, such as tuberculosis, malaria, and AIDS. However, currently used vaccines elicit strong antibody responses, but poorly stimulate CD8 cytotoxic T lymphocyte (CTL) responses. To elicit potent CTL memory, vaccines need to engage the cross-presentation pathway, and this requirement has been a crucial bottleneck in the development of subunit vaccines that engender effective T cell immunity. In this review, we focus on recent insights into DC cross-presentation and the extent to which clinically relevant vaccine adjuvants, such as aluminum-based nanoparticles, water-in oil emulsion (MF59) adjuvants, saponin-based adjuvants, and Toll-like receptor (TLR) ligands modulate DC cross-presentation efficiency. Further, we discuss the feasibility of using carbomer-based adjuvants as next generation of adjuvant platforms to elicit balanced antibody- and T-cell based immunity. Understanding of the molecular mechanism of DC cross-presentation and the mode of action of adjuvants will pave the way for rational design of vaccines for infectious diseases and cancer that require balanced antibody- and T cell-based immunity.
Topics: Adjuvants, Immunologic; Adjuvants, Vaccine; Cross-Priming; T-Lymphocytes, Cytotoxic; Vaccines, Subunit
PubMed: 35979365
DOI: 10.3389/fimmu.2022.940047 -
Nature Jul 2021Minimally invasive approaches to detect residual disease after surgery are needed to identify patients with cancer who are at risk for metastatic relapse. Circulating... (Randomized Controlled Trial)
Randomized Controlled Trial
Minimally invasive approaches to detect residual disease after surgery are needed to identify patients with cancer who are at risk for metastatic relapse. Circulating tumour DNA (ctDNA) holds promise as a biomarker for molecular residual disease and relapse. We evaluated outcomes in 581 patients who had undergone surgery and were evaluable for ctDNA from a randomized phase III trial of adjuvant atezolizumab versus observation in operable urothelial cancer. This trial did not reach its efficacy end point in the intention-to-treat population. Here we show that ctDNA testing at the start of therapy (cycle 1 day 1) identified 214 (37%) patients who were positive for ctDNA and who had poor prognosis (observation arm hazard ratio = 6.3 (95% confidence interval: 4.45-8.92); P < 0.0001). Notably, patients who were positive for ctDNA had improved disease-free survival and overall survival in the atezolizumab arm versus the observation arm (disease-free survival hazard ratio = 0.58 (95% confidence interval: 0.43-0.79); P = 0.0024, overall survival hazard ratio = 0.59 (95% confidence interval: 0.41-0.86)). No difference in disease-free survival or overall survival between treatment arms was noted for patients who were negative for ctDNA. The rate of ctDNA clearance at week 6 was higher in the atezolizumab arm (18%) than in the observation arm (4%) (P = 0.0204). Transcriptomic analysis of tumours from patients who were positive for ctDNA revealed higher expression levels of cell-cycle and keratin genes. For patients who were positive for ctDNA and who were treated with atezolizumab, non-relapse was associated with immune response signatures and basal-squamous gene features, whereas relapse was associated with angiogenesis and fibroblast TGFβ signatures. These data suggest that adjuvant atezolizumab may be associated with improved outcomes compared with observation in patients who are positive for ctDNA and who are at a high risk of relapse. These findings, if validated in other settings, would shift approaches to postoperative cancer care.
Topics: Adjuvants, Pharmaceutic; Antibodies, Monoclonal, Humanized; Biomarkers, Tumor; Circulating Tumor DNA; Gene Expression Regulation, Neoplastic; Humans; Immunotherapy; Kaplan-Meier Estimate; Neoplasm Recurrence, Local; Postoperative Care; Prognosis; Recurrence; Survival Analysis; Urinary Bladder Neoplasms
PubMed: 34135506
DOI: 10.1038/s41586-021-03642-9 -
Frontiers in Immunology 2023In the present scenario, immunization is of utmost importance as it keeps us safe and protects us from infectious agents. Despite the great success in the field of... (Review)
Review
In the present scenario, immunization is of utmost importance as it keeps us safe and protects us from infectious agents. Despite the great success in the field of vaccinology, there is a need to not only develop safe and ideal vaccines to fight deadly infections but also improve the quality of existing vaccines in terms of partial or inconsistent protection. Generally, subunit vaccines are known to be safe in nature, but they are mostly found to be incapable of generating the optimum immune response. Hence, there is a great possibility of improving the potential of a vaccine in formulation with novel adjuvants, which can effectively impart superior immunity. The vaccine(s) in formulation with novel adjuvants may also be helpful in fighting pathogens of high antigenic diversity. However, due to the limitations of safety and toxicity, very few human-compatible adjuvants have been approved. In this review, we mainly focus on the need for new and improved vaccines; the definition of and the need for adjuvants; the characteristics and mechanisms of human-compatible adjuvants; the current status of vaccine adjuvants, mucosal vaccine adjuvants, and adjuvants in clinical development; and future directions.
Topics: Humans; Adjuvants, Vaccine; Vaccines; Immunization; Vaccination; Adjuvants, Immunologic
PubMed: 36911719
DOI: 10.3389/fimmu.2023.1043109 -
Theranostics 2021Antimicrobial resistance has been a global health challenge that threatens our ability to control and treat life-threatening bacterial infections. Despite ongoing... (Review)
Review
Antimicrobial resistance has been a global health challenge that threatens our ability to control and treat life-threatening bacterial infections. Despite ongoing efforts to identify new drugs or alternatives to antibiotics, no new classes of antibiotic or their alternatives have been clinically approved in the last three decades. A combination of antibiotics and non-antibiotic compounds that could inhibit bacterial resistance determinants or enhance antibiotic activity offers a sustainable and effective strategy to confront multidrug-resistant bacteria. In this review, we provide a brief overview of the co-evolution of antibiotic discovery and the development of bacterial resistance. We summarize drug-drug interactions and uncover the art of repurposing non-antibiotic drugs as potential antibiotic adjuvants, including discussing classification and mechanisms of action, as well as reporting novel screening platforms. A pathogen-by-pathogen approach is then proposed to highlight the critical value of drug repurposing and its therapeutic potential. Finally, general advantages, challenges and development trends of drug combination strategy are discussed.
Topics: Adjuvants, Pharmaceutic; Anti-Bacterial Agents; Bacterial Infections; Drug Interactions; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Humans
PubMed: 33754035
DOI: 10.7150/thno.56205 -
Cell Research Nov 2020CD8 T cell-mediated cancer clearance is often suppressed by the interaction between inhibitory molecules like PD-1 and PD-L1, an interaction acts like brakes to prevent...
CD8 T cell-mediated cancer clearance is often suppressed by the interaction between inhibitory molecules like PD-1 and PD-L1, an interaction acts like brakes to prevent T cell overreaction under normal conditions but is exploited by tumor cells to escape the immune surveillance. Immune checkpoint inhibitors have revolutionized cancer therapeutics by removing such brakes. Unfortunately, only a minority of cancer patients respond to immunotherapies presumably due to inadequate immunity. Antitumor immunity depends on the activation of the cGAS-STING pathway, as STING-deficient mice fail to stimulate tumor-infiltrating dendritic cells (DCs) to activate CD8 T cells. STING agonists also enhance natural killer (NK) cells to mediate the clearance of CD8 T cell-resistant tumors. Therefore STING agonists have been intensively sought after. We previously discovered that manganese (Mn) is indispensable for the host defense against cytosolic dsDNA by activating cGAS-STING. Here we report that Mn is also essential in innate immune sensing of tumors and enhances adaptive immune responses against tumors. Mn-insufficient mice had significantly enhanced tumor growth and metastasis, with greatly reduced tumor-infiltrating CD8 T cells. Mechanically, Mn promoted DC and macrophage maturation and tumor-specific antigen presentation, augmented CD8 T cell differentiation, activation and NK cell activation, and increased memory CD8 T cells. Combining Mn with immune checkpoint inhibition synergistically boosted antitumor efficacies and reduced the anti-PD-1 antibody dosage required in mice. Importantly, a completed phase 1 clinical trial with the combined regimen of Mn and anti-PD-1 antibody showed promising efficacy, exhibiting type I IFN induction, manageable safety and revived responses to immunotherapy in most patients with advanced metastatic solid tumors. We propose that this combination strategy warrants further clinical translation.
Topics: Adjuvants, Pharmaceutic; Adult; Aged; Animals; Antigen Presentation; CD8-Positive T-Lymphocytes; Carcinogenesis; Dendritic Cells; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Humans; Immunity; Immunotherapy; Interferon Type I; Killer Cells, Natural; Lung; Lymphocyte Activation; Male; Manganese; Melanoma, Experimental; Membrane Proteins; Mice, Inbred C57BL; Middle Aged; Neoplasms; Nucleotidyltransferases; Organ Size; Signal Transduction; Treatment Outcome; Tumor Burden
PubMed: 32839553
DOI: 10.1038/s41422-020-00395-4 -
Cells Aug 2023In recent years, there has been a surge of interest in tumor microenvironment-associated cancer vaccine therapies. These innovative treatments aim to activate and... (Review)
Review
In recent years, there has been a surge of interest in tumor microenvironment-associated cancer vaccine therapies. These innovative treatments aim to activate and enhance the body's natural immune response against cancer cells by utilizing specific antigens present in the tumor microenvironment. The goal is to achieve a complete clinical response, where all measurable cancer cells are either eliminated or greatly reduced in size. With their potential to revolutionize cancer treatment, these therapies represent a promising avenue for researchers and clinicians alike. Despite over 100 years of research, the success of therapeutic cancer vaccines has been variable, particularly in advanced cancer patients, with various limitations, including the heterogeneity of the tumor microenvironment, the presence of immunosuppressive cells, and the potential for tumor escape mechanisms. Additionally, the effectiveness of these therapies may be limited by the variability of the patient's immune system response and the difficulty in identifying appropriate antigens for each patient. Despite these challenges, tumor microenvironment-targeted vaccine cancer therapies have shown promising results in preclinical and clinical studies and have the potential to become a valuable addition to current cancer treatment and "curative" options. While chemotherapeutic and monoclonal antibody treatments remain popular, ongoing research is needed to optimize the design and delivery of these therapies and to identify biomarkers that can predict response and guide patient selection. This comprehensive review explores the mechanisms of cancer vaccines, various delivery methods, and the role of adjuvants in improving treatment outcomes. It also discusses the historical background of cancer vaccine research and examines the current state of major cancer vaccination immunotherapies. Furthermore, the limitations and effectiveness of each vaccine type are analyzed, providing insights into the future of cancer vaccine development.
Topics: Humans; Cancer Vaccines; Immunotherapy; Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Antibodies, Monoclonal; Neoplasms
PubMed: 37681891
DOI: 10.3390/cells12172159 -
Current Opinion in Chemical Biology Oct 2022Until recently, the development of new human adjuvants was held back by a poor understanding of their mechanisms of action. The field was revolutionized by the discovery... (Review)
Review
Until recently, the development of new human adjuvants was held back by a poor understanding of their mechanisms of action. The field was revolutionized by the discovery of the toll-like receptors (TLRs), innate immune receptors that directly or indirectly are responsible for detecting pathogen-associated molecular patterns (PAMPs) and respond to them by activating innate and adaptive immune pathways. Hundreds of ligands targeting various TLRs have since been identified and characterized as vaccine adjuvants. This work has important implications not only for the development of vaccines against infectious diseases but also for immuno-therapies against cancer, allergy, Alzheimer's disease, drug addiction and other diseases. Each TLR has its own specific tissue localization and downstream gene signalling pathways, providing researchers the opportunity to precisely tailor adjuvants with specific immune effects. TLR agonists can be combined with other TLR or alternative adjuvants to create combination adjuvants with synergistic or modulatory effects. This review provides an introduction to the various classes of TLR adjuvants and their respective signalling pathways. It provides an overview of recent advancements in the TLR field in the past 2-3 years and discusses criteria for selecting specific TLR adjuvants based on considerations, such as disease mechanisms and correlates of protection, TLR immune biasing capabilities, route of administration, antigen compatibility, new vaccine technology platforms, and age- and species-specific effects.
Topics: Adjuvants, Immunologic; Adjuvants, Vaccine; Humans; Neoplasms; Pathogen-Associated Molecular Pattern Molecules; Toll-Like Receptors; Vaccines
PubMed: 35785601
DOI: 10.1016/j.cbpa.2022.102172 -
Expert Review of Vaccines May 2021The importance of vaccine thermostability has been discussed in the literature. Nevertheless, the challenge of developing thermostable vaccine adjuvants has sometimes... (Review)
Review
INTRODUCTION
The importance of vaccine thermostability has been discussed in the literature. Nevertheless, the challenge of developing thermostable vaccine adjuvants has sometimes not received appropriate emphasis. Adjuvants comprise an expansive range of particulate and molecular compositions, requiring innovative thermostable formulation and process development approaches.
AREAS COVERED
Reports on efforts to develop thermostable adjuvant-containing vaccines have increased in recent years, and substantial progress has been made in enhancing the stability of the major classes of adjuvants. This narrative review summarizes the current status of thermostable vaccine adjuvant development and looks forward to the next potential developments in the field.
EXPERT OPINION
As adjuvant-containing vaccines become more widely used, the unique challenges associated with developing thermostable adjuvant formulations merit increased attention. In particular, more focused efforts are needed to translate promising proof-of-concept technologies and formulations into clinical products.
Topics: Adjuvants, Immunologic; Adjuvants, Vaccine; Humans; Vaccines
PubMed: 33724133
DOI: 10.1080/14760584.2021.1902314 -
Methods in Molecular Biology (Clifton,... 2023Self-adjuvanting vaccines, covalent conjugates between antigens and adjuvants, are chemically well-defined compared with conventional vaccines formulated through mixing... (Review)
Review
Self-adjuvanting vaccines, covalent conjugates between antigens and adjuvants, are chemically well-defined compared with conventional vaccines formulated through mixing antigens with adjuvants. Innate immune receptor ligands effectively induce acquired immunity through the activation of innate immunity, thereby enhancing host immune responses. Thus, innate immune receptor ligands are often used as adjuvants in self-adjuvanting vaccines. In a self-adjuvanting vaccine, the covalent linkage of antigen and adjuvant enables their simultaneous uptake into immune cells where the adjuvant consequently induces antigen-specific immune responses. Importantly, self-adjuvanting vaccines do not require immobilization to carrier proteins or co-administration of additional adjuvants and thus avoid inducing undesired immune responses. Because of these excellent properties, self-adjuvanting vaccines are expected to be candidates for next-generation vaccines. Here, we take an overview of vaccine adjuvants, mainly focusing on those utilized in self-adjuvanting vaccines and then we review recent reports on self-adjuvanting conjugate vaccines.
Topics: Vaccines, Conjugate; Vaccines; Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Immunity, Innate; Ligands
PubMed: 36587070
DOI: 10.1007/978-1-0716-2910-9_5