Diversity of regulatory B cells: Markers and functions.

Regulatory B cells (Bregs) are a functionally distinct B-cell subset involved in the maintenance of homeostasis and inhibition of inflammation. Studies, from the last two decades, have increased our understanding of cellular and molecular mechanisms involved in their generation, function, and to a certain extent phenotype. Current research endeavours to unravel the causes and consequences of Breg defects in disease, with increasing evidence highlighting the relevance of Bregs in promoting tumorigenic responses. Here we provide historical and emerging findings of the significance of Bregs in autoimmunity and transplantation, and how these insights have translated into the cancer field.

miRNA-Targeted Vaccines: A Promising Approach for Viral Attenuation and Immunogenicity Enhancement.

MicroRNAs (miRNAs) have emerged as a significant tool in the realm of vaccinology, offering novel approaches to vaccine development. This study investigates the potential of miRNAs in the development of advanced vaccines, with an emphasis on how they regulate immune response and control viral replication. We go over the molecular features of miRNAs, such as their capacity to direct post-transcriptional regulation toward mRNAs, hence regulating the expression of genes in diverse tissues and cells. This property is harnessed to develop live attenuated vaccines that are tissue-specific, enhancing safety and immunogenicity. The review highlights recent advancements in using miRNA-targeted vaccines against viruses like influenza, poliovirus, and tick-borne encephalitis virus, demonstrating their attenuated replication in specific tissues while retaining immunogenicity. We also explored the function of miRNAs in the biology of cancer, highlighting their potential to develop cancer vaccines through targeting miRNAs that are overexpressed in tumor cells. The difficulties in developing miRNA vaccines are also covered in this work, including delivery, stability, off-target effects, and the requirement for individualized cancer treatment plans. We wrap off by discussing the potential of miRNA vaccines and highlighting how they will influence the development of vaccination techniques for cancer and infectious diseases in the future.

The Triad of Sleep, Immunity, and Cancer: A Mediating Perspective.

The triadic interplay between sleep, immunity, and cancer represents a growing area of biomedical research with significant clinical implications. This review synthesizes the current knowledge on how sleep influences immune function, the immune system's role in cancer dynamics, and the direct connections between sleep patterns and cancer risk. After a comprehensive overview of the interrelationships among these three domains, the mechanisms of sleep in immune function are described, detailing how sleep regulates the immune system, the effects of sleep duration and quality on immune responses, and the underlying molecular and cellular mechanisms. Also, the complex relationship between immunity and cancer is explored, highlighting the immune system's role in cancer prevention and progression, immune surveillance, tumor microenvironment, and the implications of immunodeficiency and immune modulation on cancer risk. The direct connections between sleep and cancer are then described, presenting epidemiological evidence linking sleep patterns to cancer risk, biological mechanisms that influence cancer development, and the role of sleep disorders in cancer prognosis. The mediating role of sleep between immunity and cancer is highlighted, proposing hypothesized pathways, summarizing evidence from experimental and clinical studies, and evaluating the impact of sleep interventions on immune function and cancer outcomes. This review concludes by discussing the clinical implications and future directions, emphasizing the potential for sleep-based interventions in cancer prevention and treatment, the integration of sleep management in oncology and immunotherapy, and outlining a future research agenda. This agenda includes understanding the mechanisms of the sleep-immunity-cancer interplay, conducting epidemiological studies on sleep and cancer risk, assessing the impact of sleep management in cancer treatment protocols, exploring sleep and tumor microenvironment interactions, and considering policy and public health implications. Through a detailed examination of these interconnected pathways, this review underscores the critical importance of sleep in modulating immune function and cancer outcomes, advocating for interdisciplinary research and clinical strategies to harness this knowledge for improved health outcomes.

Orchestrated metal-coordinated carrier-free celastrol hydrogel intensifies T cell activation and regulates response to immune checkpoint blockade for synergistic chemo-immunotherapy.

The challenges generated by insufficient T cell activation and infiltration have constrained the application of immunotherapy. Making matters worse, the complex tumor microenvironment (TME), resistance to apoptosis collectively poses obstacles for cancer treatment. The carrier-free small molecular self-assembly strategy is a current research hotspot to overcome these challenges. This strategy can transform multiple functional agents into sustain-released hydrogel without the addition of any excipients. Herein, a coordination and hydrogen bond mediated tricomponent hydrogel (Cel hydrogel) composed of glycyrrhizic acid (GA), copper ions (Cu2+) and celastrol (Cel) was initially constructed. The hydrogel can regulate TME by chemo-dynamic therapy (CDT), which increases reactive oxygen species (ROS) in conjunction with GA and Cel, synergistically expediting cellular apoptosis. What's more, copper induced cuproptosis also contributes to the anti-tumor effect. In terms of regulating immunity, ROS generated by Cel hydrogel can polarize tumor-associated macrophages (TAMs) into M1-TAMs, Cel can induce T cell proliferation as well as activate DC mediated antigen presentation, which subsequently induce T cell proliferation, elevate T cell infiltration and enhance the specific killing of tumor cells, along with the upregulation of PD-L1 expression. Upon co-administration with aPD-L1, this synergy mitigated both primary and metastasis tumors, showing promising clinical translational value.

Immunophenotypical Characterization of Limbal Mesenchymal Stromal Cell Subsets during In Vitro Expansion.

Limbal mesenchymal stromal cells (LMSCs) reside in the limbal niche, supporting corneal integrity and facilitating regeneration. While mesenchymal stem/stromal cells (MSCs) are used in regenerative therapies, there is limited knowledge about LMSC subpopulations and their characteristics. This study characterized human LMSC subpopulations through the flow cytometric assessment of fifteen cell surface markers, including MSC, wound healing, immune regulation, ASC, endothelial, and differentiation markers. Primary LMSCs were established from remnant human corneal transplant specimens and passaged eight times to observe changes during subculture. The results showed the consistent expression of typical MSC markers and distinct subpopulations with the passage-dependent expression of wound healing, immune regulation, and differentiation markers. High CD166 and CD248 expressions indicated a crucial role in ocular surface repair. CD29 expression suggested an immunoregulatory role. Comparable pigment-epithelial-derived factor (PEDF) expression supported anti-inflammatory and anti-angiogenic roles. Sustained CD201 expression indicated maintained differentiation capability, while VEGFR2 expression suggested potential endothelial differentiation. LMSCs showed higher VEGF expression than fibroblasts and endothelial cells, suggesting a potential contribution to ocular surface regeneration through the modulation of angiogenesis and inflammation. These findings highlight the heterogeneity and multipotent potential of LMSC subpopulations during in vitro expansion, informing the development of standardized protocols for regenerative therapies and improving treatments for ocular surface disorders.

Immunoregulatory paracrine effect of mesenchymal stem cells and mechanism in the treatment of osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disease caused by chronic inflammation that damages articular cartilage. At present, the treatment of OA includes drug therapy to relieve symptoms and joint replacement therapy for advanced OA. However, these palliatives cannot truly block the progression of the disease from the immunological pathogenesis of OA. In recent years, bone marrow mesenchymal stem cell (BMSC) transplantation has shown great potential in tissue engineering repair. In addition, many studies have shown that BMSC paracrine signals play an important role in the treatment of OA through immune regulation and suppressing inflammation. At present, the mechanism of inflammation-induced OA and the use of BMSC transplantation in joint repair have been reviewed, but the mechanism and significance of BMSC paracrine signals in the treatment of OA have not been fully reviewed. Therefore, this article focused on the latest research progress on the paracrine effects of BMSCs in the treatment of OA and the related mechanisms by which BMSCs secrete cytokines to inhibit the inflammatory response, regulate immune balance, and promote cell proliferation and differentiation. In addition, the application potential of BMSC-Exos as a new type of cell-free therapy for OA is described. This review aimed to provide systematic theoretical support for the clinical application of BMSC transplantation in the treatment of OA.

The immunoregulatory role of monocytes and thrombomodulin in myelodysplastic neoplasms.

Myelodysplastic neoplasms (MDS) are clonal disorders of the myeloid lineage leading to peripheral blood cytopenias. Dysregulation of innate immunity is hypothesized to be a potent driver of MDS. A recent study revealed increased thrombomodulin (TM) expression on classical monocytes in MDS, which was associated with prolonged survival. TM is a receptor with immunoregulatory capacities, however, its exact role in MDS development remains to be elucidated. In this review we focus on normal monocyte biology and report on the involvement of monocytes in myeloid disease entities with a special focus on MDS. Furthermore, we delve into the current knowledge on TM and its function in monocytes in health and disease and explore the role of TM-expressing monocytes as driver, supporter or epiphenomenon in the MDS bone marrow environment.

MiR-210, not let-7, regulates Akt gene expression against Vibrio splendidus infection in the sea cucumber Apostichopus japonicus.

The immune regulatory roles of microRNAs (miRNAs) have recently attracted considerable attention. Bioinformatics prediction revealed that both let-7 and miR-210 provide potential binding sites for the Akt (rac-alpha serine/threonine-protein kinase) gene sequence in the sea cucumber Apostichopus japonicus (termed AjAkt). In this study, we first used a dual-luciferase reporter assay and functional validation techniques to verify the interactions between these two miRNAs (let-7 and miR-210) and AjAkt, and then investigated the functions of the validated miRNA/mRNA pair as part of the innate immune response against Vibrio splendidus infection. We found that AjAkt interacts with miR-210 rather than let-7, and miR-210 negatively regulates the expression of AjAkt. From 8 to 48 h after infection with V. splendidus, opposite trends were observed in the expression levels of miR-210 and AjAkt (mRNA and protein) in coelomocytes, suggesting that the miR-210/AjAkt pair is involved in immune regulation during this period after infection. Both AjAkt silencing and miR-210 overexpression enhanced the phagocytic capacity and reduced the infectivity of A. japonicus after pathogen infection, suggesting that the miR-210/AjAkt pair may regulate the innate immune response of A. japonicus by altering phagocytic capacity. The findings of this study enrich our knowledge of the role of miRNA/mRNA pairs in immune regulation in sea cucumbers and provide insights into the molecular mechanisms of the innate immune response in marine echinoderms.

Targeting gut-microbiota for gastric cancer treatment: a systematic review.

Background: Preclinical research has identified the mechanisms via which bacteria influence cancer treatment outcomes. Clinical studies have demonstrated the potential to modify the microbiome in cancer treatment. Herein, we systematically analyze how gut microorganisms interact with chemotherapy and immune checkpoint inhibitors, specifically focusing on how gut bacteria affect the pharmacokinetics and pharmacodynamics of cancer treatment. Method: This study searched Web of Science, Scopus, and PubMed until August 2023. Studies were screened by their title and abstract using the Rayyan intelligent tool for systematic reviews. Quality assessment of studies was done using the JBI critical appraisal tool. Result: Alterations in the gut microbiome are associated with gastric cancer and precancerous lesions. These alterations include reduced microbial alpha diversity, increased bacterial overgrowth, and decreased richness and evenness of gastric bacteria. Helicobacter pylori infection is associated with reduced richness and evenness of gastric bacteria, while eradication only partially restores microbial diversity. The gut microbiome also affects the response to cancer treatments, with higher abundances of Lactobacillus associated with better response to anti-PD-1/PD-L1 immunotherapy and more prolonged progression-free survival. Antibiotic-induced gut microbiota dysbiosis can reduce the anti-tumor efficacy of 5-Fluorouracil treatment, while probiotics did not significantly enhance it. A probiotic combination containing Bifidobacterium infantis, Lactobacillus acidophilus, Enterococcus faecalis, and Bacillus cereus can reduce inflammation, enhance immunity, and restore a healthier gut microbial balance in gastric cancer patients after partial gastrectomy. Conclusion: Probiotics and targeted interventions to modulate the gut microbiome have shown promising results in cancer prevention and treatment efficacy.Systematic review registration: https://osf.io/6vcjp.

The role of interleukin-2 in graft-versus-host disease pathogenesis, prevention and therapy.

Graft-versus-host disease (GVHD) is a significant complication following allogeneic hematopoietic cell transplantation (allo-HCT), posing substantial risks to patient survival. In the late follow-up phase of transplanted patients, GVHD is also a major cause of morbidity and disability, mostly due to low response to first-line steroids and the lack of effective standard therapies in the second line. This review provides a description of GVHD pathogenesis, with a focus on the central role of Interleukin-2 (IL-2). IL-2 is one of the critical mediators in the complex pathogenesis of GVHD, contributing to the intricate balance between regulatory T cells (Tregs) and effector T cells (Teffs). Due to this pivotal role, several studies investigate the potential of IL-2 as a therapeutic option for GVHD management. We discuss the outcomes of low-dose IL-2 therapies and their impact on Treg proliferation and steroid dependency reduction. Additionally, the effects of combining IL-2 with other treatments, such as extracorporeal photopheresis (ECP) and Treg-enriched lymphocyte infusions, are highlighted. Novel approaches, including modified IL-2 complexes and IL-2 receptor blockade, are explored for their potential in selectively enhancing Treg function and limiting Teff activation. The evolving understanding of IL-2's pivotal role in immune regulation presents promising prospects for applying treatment and prevention strategies for GVHD.

Increased IFN-ß Indicates Better Survival in Hepatocellular Carcinoma Treated with Radiotherapy.

Pre-clinical data suggest that type I interferon (IFN) responsiveness is essential for the antitumor effects of radiotherapy (RT). However, its clinical value remains unclear. This study aimed to explore this from a clinical perspective. In cohort 1, data from 152 hepatocellular carcinoma (HCC) patients who received RT were analyzed. Blood samples were taken 1 day before and 2 weeks after RT. RT was found to increase serum levels of IFN-ß (a subtype of IFN-I) in HCC patients (3.42 ± 1.57 to 5.51 ± 2.11 pg/mL, p < 0.01), particularly in those with favorable responses. Higher post-RT serum IFN-ß levels (≥ 4.77 pg/mL) were associated with better progression-free survival (HR = 0.58, p < 0.01). Cohort 2 included 46 HCC patients, including 23 who underwent preoperative RT and 23 matched control HCC who received surgical resection without RT. Formalin-fixed paraffin-embedded samples were obtained. Neoadjuvant RT significantly increased IFN-ß expression in tumor tissues compared to direct surgery (8.13% ± 5.19% to 15.10% ± 5.89%, p < 0.01). Higher post-RT IFN-ß (> median) indicated better disease-free survival (p = 0.049). Additionally, increased CD11c+MHCII+CD141+ antigen presenting cell subsets and CD103+CD39+CD8+ tumor-infiltrating lymphocytes were found in the higher IFN-ß group (p = 0.02, p = 0.03), which may contribute to the favorable prognosis in higher IFN-ß group. Collectively, these findings suggest that IFN-ß response activated by radiation may serve as a prognostic biomarker for HCC patients undergoing RT.

Exploratory Investigation of Zinc-Modified Borosilicate Bioactive Glass: A New Methodology for Its Biocompatibility, Immunoregulation, and Pro-Angiogenic Property Evaluation.

The assessment of biodegradable materials, such as bioactive glass, under the existing ISO 10993 standard test methods poses a significant challenge due to potential cell viability impairment caused by the accumulation of degraded products in a static environment. Therefore, innovative methodologies are urgently needed to tailor the unique biodegradation characteristics of these materials, providing more precise and scientific insights into biosafety and efficacy verification. Motivation by its bidirectional regulation of angiogenesis and immunity, zinc (Zn) was incorporated into sol-gel-derived borosilicate bioactive glasses (SBSGs) to fabricate Zn-incorporated borosilicate bioactive glasses (SBSG-Zn) to complement the tissue repair capabilities of bioactive glasses. Both SBSG and SBSG-Zn glasses consist of nanosized particles, slit mesoporous pores, high specific surface areas, and bioreactivity. In vitro comparative analysis, conducted according to ISO 10993 standards, demonstrates that only at suitable dilution rates─such as the 8-fold dilution employed in this study─do extracts of SBSG and SBSG-Zn glasses exhibit low cytotoxicity when cultured with human umbilical vein endothelial cells (HUVECs). Notably, SBSG-Zn glasses show optimal promotion of angiogenic gene expression in HUVECs. Furthermore, within an appropriate concentration range of released ions, SBSG-Zn glass extracts not only promote cell survival but also modulate the expression of anti-inflammatory genes while simultaneously inhibiting pro-inflammatory genes concurrently. After being implanted in rat subcutaneous defect models, both SBSG and SBSG-Zn glasses demonstrated the local immunoregulation and angiogenic effects. SBSG-Zn stands out by demonstrating superior modulation of M1/M2 polarization in macrophages as validated by altered secretion of key factors in macrophages and expression of relevant growth factors in HUVECs. These findings underscore the potential for convenient manipulation of localized angiogenic and immunoregulation through the incorporation of zinc into bioactive glass, emphasizing the importance of ensuring the appropriate ion doses are applied for achieving optimal therapeutic efficiency.

Crystal structure of NYN domain of Human KHNYN in complex with single strand RNA.

KHNYN protein with a KH-like domain and a NYN endoribonuclease domain interacts with Zinc-finger antiviral protein (ZAP). ZAP isoforms recognize viral or cellular RNAs and recruit KHNYN to form the ZAP: KHNYN complex. Although the structures of several PIN/NYN domains have been determined, the precise substrate RNA binding mode remains poorly understood. This study presents the crystal structure of a complex of the NYN domain of KHNYN and a 7mer RNA from interferon lambda3 (IFNL3). Our structural analysis reveals that NYN domain of human KHNYN shares structural similarities with other NYN domains of ZC3H12àC proteins. The RNA is bound in the central groove region of the protein, facilitated by interactions including coordination by two Mg2+ ions, hydrophobic interactions, and hydrogen bonds. In the observed RNA-protein complex, the U5, A6, and U7 bases are stacked on top of one another, while U3 and U4 bases adopt an "open" conformation (as opposed to base-stacked), forming a U-shaped overall structure. Mutagenesis studies underscore the significance of residues involved in RNA binding for RNase activity. Interestingly, NYN domain of human KHNYN forms a head-to-tail dimer in the crystal, a structural feature also observed in other homologous PIN/NYN proteins, with a residue from the symmetry mate contributing to hydrophobic interactions with the bound RNA.

Gut microbiota and skin pathologies: Mechanism of the gut-skin axis in atopic dermatitis and psoriasis.

Atopic dermatitis (AD) and psoriasis are chronic skin diseases with a global impact, posing significant challenges to public health systems and severely affecting patients' quality of life. This review delves into the key role of the gut microbiota in these diseases, emphasizing the importance of the gut-skin axis in inflammatory mediators and immune regulation and revealing a complex bidirectional communication system. We comprehensively assessed the pathogenesis, clinical manifestations, and treatment strategies for AD and psoriasis, with a particular focus on how the gut microbiota and their metabolites influence disease progression via the gut-skin axis. In addition, personalized treatment plans based on individual patient microbiome characteristics have been proposed, offering new perspectives for future treatment approaches. We call for enhanced interdisciplinary cooperation to further explore the interactions between gut microbiota and skin diseases and to assess the potential of drugs and natural products in modulating the gut-skin axis, aiming to advance the treatment of skin diseases.

Dissecting the emerging role of cancer-associated adipocyte-derived cytokines in remodeling breast cancer progression.

Breast cancer has been reported to transcend lung cancer as the most commonly diagnosed cancer in women all over the world. Adipocytes, serving as energy storage and endocrine cells, are the major stromal cells in the breast. Cancer-associated adipocytes (CAAs) are adjacent and dedifferentiated adipocytes located at the invasive front of human breast tumors. Adipocytes can transform into CAA phenotype with morphological and biological changes under the remodeling of breast cancer cells. CAAs play an essential role in breast cancer progression, including remodeling the tumor microenvironment (TME), regulating immunity, and interacting with breast cancer cells. CAAs possess peculiar secretomes and are accordingly capable to promote proliferation, invasiveness, angiogenesis, metastasis, immune escape, and drug resistance of breast cancer cells. There is a complex and coordinated crosstalk among CAAs, immune cells, and breast cancer cells. CAAs can release a variety of cytokines, including IL-6, IL-8, IL-1ß, CCL5, CCL2, VEGF, G-CSF, IGF-1, and IGFBP, thereby promoting immune cell recruitment and macrophage polarization, and ultimately stimulating malignant behaviors in breast cancer cells. Here, we aim to provide a comprehensive description of CAA-derived cytokines, including their impact on cancer cell behaviors, immune regulation, breast cancer diagnosis, and treatment. A deeper understanding of CAA performance and interactions with specific TME cell populations will provide better strategies for cancer treatment and breast reconstruction after mastectomy.

A case of Melkersson-Rosenthal syndrome with temporomandibular joint osteoarthritis: multidisciplinary treatment and autoimmune etiological hypothesis.

BACKGROUND: Melkersson-Rosenthal syndrome (MRS) is a rare neuro-mucocutaneous disorder characterized by recurrent edema, facial palsies, and nerve dysfunctions often associated with the plicata tongue. Although the etiology of MRS is not well understood, there is growing evidence suggesting an autoimmune involvement. CASE PRESENTATION: This paper presents a case report of a 25-year-old male with MRS as the initial symptom, followed by temporomandibular joint osteoarthritis (TMJ-OA). A comprehensive diagnosis and multidisciplinary treatment approach including surgery, local injections, and oral medication were implemented, resulting in a favorable prognosis. CONCLUSIONS: These findings support the hypothesis that MRS is a systemic granulomatous disease caused by autoimmunity, which may also influence the occurrence and development of TMJ-OA through immune-related mechanisms. This study emphasizes the significance of systemic immune regulation in the treatment of patients with MRS and TMJ-OA comorbid conditions.

Human milk oligosaccharides in preventing food allergy: A review through gut microbiota and immune regulation.

Food allergy (FA) has increasingly attracted global attention in past decades. However, the mechanism and effect of FA are complex and varied, rendering it hard to prevention and management. Most of the allergens identified so far are macromolecular proteins in food and may have potential cross-reactions. Human milk oligosaccharides (HMOs) have been regarded as an ideal nutrient component for infants, as they can enhance the immunomodulatory capacity to inhibit the progress of FA. HMOs may intervene in the development of allergies by modifying gut microbiota and increasing specific short-chain fatty acids levels. Additionally, HMOs could improve the intestinal permeability and directly or indirectly regulate the balance of T helper cells and regulatory T cells by enhancing the inflammatory signaling pathways to combat FA. This review will discuss the influence factors of FA, key species of gut microbiota involved in FA, types of FA, and profiles of HMOs and provide evidence for future research trends to advance HMOs as potential therapeutic aids in preventing the progress of FA.

Therapeutic potential of plant-derived natural compounds in Alzheimer's disease: Targeting microglia-mediated neuroinflammation.

Microglia are resident immune cells of the central nervous system (CNS) with roles in sensing, housekeeping, and defense. Exploring the role of microglia in the occurrence and development of Alzheimer's disease (AD) and the possible therapeutic mechanism of plant-derived natural compounds (PDNCs) that regulate microglia-associated neuroinflammation may potentially help in elucidating the pathogenesis of AD and provide novel insights for its treatment. This review explores the role of abnormal microglial activation and its dominant neuroinflammatory response, as well as the activation of their target receptors and signaling pathways in AD pathogenesis. Additionally, we report an update on the potential pharmacological mechanisms of multiple PDNCs in modulating microglia-associated neuroinflammation in AD treatment. Dysregulated activation of microglial receptors and their downstream pathways impaired immune homeostasis in animal models of AD. Multiple signaling pathways, such as mitogen-activated protein kinase (MAPK), nuclear factor kappa light chain enhancer of activated B cells (NF-κB), and Toll-like receptors, play important roles in microglial activation and can exacerbate microglia-mediated neuroinflammation. PDNCs, such as magnolol, stigmasterol, matrine, naringenin, naringin, and resveratrol, can delay the progression of AD by inhibiting the proinflammatory receptors of microglia, activating its anti-inflammatory receptors, regulating the receptors related to ß-amyloid (Aß) clearance, reversing immune dysregulation, and maintaining the immune homeostasis of microglial downstream pathways. This review summarizes the mechanisms by which microglia cause chronic inflammation in AD and evaluates the beneficial effects of PDNCs on immune regulation in AD by regulating microglial receptors and their downstream pathways.

Lithium Ions as Modulators of Complex Biological Processes: The Conundrum of Multiple Targets, Responsiveness and Non-Responsiveness, and the Potential to Prevent or Correct Dysregulation of Systems during Aging and in Disease.

Lithium is one of the lightest elements on Earth and it has been in the environment since the formation of the galaxy. While a common element, it has not been found to be an essential element in biological processes, ranging from single cell organisms to Homo sapiens. Instead, at an early stage of evolution, organisms committed to a range of elements such as sodium, potassium, calcium, magnesium, zinc, and iron to serve essential functions. Such ions serve critical functions in ion channels, as co-factors in enzymes, as a cofactor in oxygen transport, in DNA replication, as a storage molecule in bone and liver, and in a variety of other roles in biological processes. While seemingly excluded from a major essential role in such processes, lithium ions appear to be able to modulate a variety of biological processes and "correct" deviation from normal activity, as a deficiency of lithium can have biological consequences. Lithium salts are found in low levels in many foods and water supplies, but the effectiveness of Li salts to affect biological systems came to recent prominence with the work of Cade, who reported that administrating Li salts calmed guinea pigs and was subsequently effective at relatively high doses to "normalize" a subset of patients with bipolar disorders. Because of its ability to modulate many biological pathways and processes (e.g., cyclic AMP, GSK-3beta, inositol metabolism, NaK ATPases, neuro processes and centers, immune-related events, respectively) both in vitro and in vivo and during development and adult life, Li salts have become both a useful tool to better understand the molecular regulation of such processes and to also provide insights into altered biological processes in vivo during aging and in disease states. While the range of targets for lithium action supports its possible role as a modulator of biological dysregulation, it presents a conundrum for researchers attempting to elucidate its specific primary target in different tissues in vivo. This review will discuss aspects of the state of knowledge regarding some of the systems that can be influenced, focusing on those involving neural and autoimmunity as examples, some of the mechanisms involved, examples of how Li salts can be used to study model systems, as well as suggesting areas where the use of Li salts could lead to additional insights into both disease mechanisms and natural processes at the molecular and cell levels. In addition, caveats regarding lithium doses used, the strengths and weaknesses of rodent models, the background genetics of the strain of mice or rats employed, and the sex of the animals or the cells used, are discussed. Low-dose lithium may have excellent potential, alone or in combination with other interventions to prevent or alleviate aging-associated conditions and disease progression.