Navigating the Modern Landscape of Sepsis: Advances in Diagnosis and Treatment.

Sepsis poses a significant threat to human health due to its high morbidity and mortality rates worldwide. Traditional diagnostic methods for identifying sepsis or its causative organisms are time-consuming and contribute to a high mortality rate. Biomarkers have been developed to overcome these limitations and are currently used for sepsis diagnosis, prognosis prediction, and treatment response assessment. Over the past few decades, more than 250 biomarkers have been identified, a few of which have been used in clinical decision-making. Consistent with the limitations of diagnosing sepsis, there is currently no specific treatment for sepsis. Currently, the general treatment for sepsis is conservative and includes timely antibiotic use and hemodynamic support. When planning sepsis-specific treatment, it is important to select the most suitable patient, considering the heterogeneous nature of sepsis. This comprehensive review summarizes current and evolving biomarkers and therapeutic approaches for sepsis.

An injectable magnesium-loaded hydrogel releases hydrogen to promote osteoporotic bone repair via ROS scavenging and immunomodulation.

Background: The repair of osteoporotic bone defects remains challenging due to excessive reactive oxygen species (ROS), persistent inflammation, and an imbalance between osteogenesis and osteoclastogenesis. Methods: Here, an injectable H2-releasing hydrogel (magnesium@polyethylene glycol-poly(lactic-co-glycolic acid), Mg@PEG-PLGA) was developed to remodel the challenging bone environment and accelerate the repair of osteoporotic bone defects. Results: This Mg@PEG-PLGA gel shows excellent injectability, shape adaptability, and phase-transition ability, can fill irregular bone defect areas via minimally invasive injection, and can transform into a porous scaffold in situ to provide mechanical support. With the appropriate release of H2 and magnesium ions, the 2Mg@PEG-PLGA gel (loaded with 2 mg of Mg) displayed significant immunomodulatory effects through reducing intracellular ROS, guiding macrophage polarization toward the M2 phenotype, and inhibiting the IκB/NF-κB signaling pathway. Moreover, in vitro experiments showed that the 2Mg@PEG-PLGA gel inhibited osteoclastogenesis while promoting osteogenesis. Most notably, in animal experiments, the 2Mg@PEG-PLGA gel significantly promoted the repair of osteoporotic bone defects in vivo by scavenging ROS and inhibiting inflammation and osteoclastogenesis. Conclusions: Overall, our study provides critical insight into the design and development of H2-releasing magnesium-based hydrogels as potential implants for repairing osteoporotic bone defects.

Harnessing immunity: Immunomodulatory therapies in COVID-19.

An overly exuberant immune response, characterized by a cytokine storm and uncontrolled inflammation, has been identified as a significant driver of severe coronavirus disease 2019 (COVID-19) cases. Consequently, deciphering the intricacies of immune dysregulation in COVID-19 is imperative to identify specific targets for intervention and modulation. With these delicate dynamics in mind, immunomodulatory therapies have emerged as a promising avenue for mitigating the challenges posed by COVID-19. Precision in manipulating immune pathways presents an opportunity to alter the host response, optimizing antiviral defenses while curbing deleterious inflammation. This review article comprehensively analyzes immunomodulatory interventions in managing COVID-19. We explore diverse approaches to mitigating the hyperactive immune response and its impact, from corticosteroids and non-steroidal drugs to targeted biologics, including anti-viral drugs, cytokine inhibitors, JAK inhibitors, convalescent plasma, monoclonal antibodies (mAbs) to severe acute respiratory syndrome coronavirus 2, cell-based therapies (i.e., CAR T, etc.). By summarizing the current evidence, we aim to provide a clear roadmap for clinicians and researchers navigating the complex landscape of immunomodulation in COVID-19 treatment.

Unraveling colorectal cancer prevention: The vitamin D - gut flora - immune system nexus.

Colorectal cancer (CRC) is one of the most common cancers diagnosed in the world. Although environmental and genetic factors play a major role in the pathogenesis of CRC, extensive research has suggested that vitamin D may play a pivotal role in the development of CRC. Vitamin D, primarily obtained through sunlight exposure, dietary sources, and supplements, has long been recognized for its essential functions in maintaining health, including immune regulation. This article delves into the intricate relationship between vitamin D, the immune system, gut flora, and the prevention of CRC. It presents a synthesis of epidemiological data, experimental studies, and clinical trials, highlighting the mechanisms by which vitamin D influences immune cell function, cytokine production, and inflammation. By enhancing the immune system's surveillance and anti-tumor activity, vitamin D may offer a promising avenue for CRC prevention. Furthermore, this comprehensive review delves into the prospective clinical applications of vitamin D supplementation and delineates the forthcoming avenues of research in this dynamic domain. Additionally, the paper tentatively outlines a spectrum of prophylactic impacts of vitamin D on CRC, emphasizing its significant potential in reducing CRC risk through shedding light on its mechanisms, encompassing antineoplastic mechanisms, influences on the immune system, and modulation of the gut microbiome.

The effect of previous SARS-CoV-2 infection on systemic immune responses in individuals with tuberculosis.

Background: The impact of previous SARS-CoV-2 infection on the systemic immune response during tuberculosis (TB) disease has not been explored. Methods: An observational, cross-sectional cohort was established to evaluate the systemic immune response in persons with pulmonary tuberculosis with or without previous SARS-CoV-2 infection. Those participants were recruited in an outpatient referral clinic in Rio de Janeiro, Brazil. TB was defined as a positive Xpert-MTB/RIF Ultra and/or a positive culture of Mycobacterium tuberculosis from sputum. Stored plasma was used to perform specific serology to identify previous SARS-CoV-2 infection (TB/Prex-SCoV-2 group) and confirm the non- infection of the tuberculosis group (TB group). Plasmatic cytokine/chemokine/growth factor profiling was performed using Luminex technology. Tuberculosis severity was assessed by clinical and laboratory parameters. Participants from TB group (4.55%) and TB/Prex-SCoV-2 (0.00%) received the complete COVID-19 vaccination. Results: Among 35 participants with pulmonary TB, 22 were classified as TB/Prex-SCoV-2. The parameters associated with TB severity, together with hematologic and biochemical data were similar between the TB and TB/Prex-SCoV-2 groups. Among the signs and symptoms, fever and dyspnea were significantly more frequent in the TB group than the TB/Prex-SCoV-2 group (p < 0,05). A signature based on lower amount of plasma EGF, G-CSF, GM-CSF, IFN-α2, IL-12(p70), IL-13, IL-15, IL-17, IL-1ß, IL-5, IL-7, and TNF-ß was observed in the TB/Prex-SCoV-2 group. In contrast, MIP-1ß was significantly higher in the TB/Prex-SCoV-2 group than the TB group. Conclusion: TB patients previously infected with SARS-CoV-2 had an immunomodulation that was associated with lower plasma concentrations of soluble factors associated with systemic inflammation. This signature was associated with a lower frequency of symptoms such as fever and dyspnea but did not reflect significant differences in TB severity parameters observed at baseline.

Association Between Gut and Nasal Microbiota and Allergic Rhinitis: A Systematic Review.

Allergic rhinitis is a chronic non-infectious inflammation of the nasal mucosa mediated by specific IgE. Recently, the human microbiome has drawn broad interest as a potential new target for treating this condition. This paper succinctly summarizes the main findings of 17 eligible studies published by February 2024, involving 1044 allergic rhinitis patients and 954 healthy controls from 5 countries. These studies examine differences in the human microbiome across important mucosal interfaces, including the nasal and intestinal areas, between patients and controls. Overall, findings suggest variations in the gut microbiota between allergic rhinitis patients and healthy individuals, although the specific bacterial taxa that significantly changed were not always consistent across studies. Due to the limited scope of existing research and patient coverage, the relationship between the nasal microbiome and allergic rhinitis remains inconclusive. The article discusses the potential immune-regulating role of the gut microbiome in allergic rhinitis. Further well-designed clinical trials with large-scale recruitment of allergic rhinitis patients are encouraged.

High viral loads combined with inflammatory markers predict disease severity in hospitalized COVID-19 patients: Results from the NOR-Solidarity trial.

OBJECTIVES: To investigate temporal changes in the association between SARS-CoV2 viral load (VL) and markers of inflammation during hospitalization, as well as the ability of these markers alone or in combination to predict severe outcomes. METHODS: Serial oropharyngeal and blood samples were obtained from hospitalized COVID-19 patients (n = 160). Levels of inflammatory markers and oropharyngeal VL were measured during hospitalization (admission, days 3-5, and days 7-10) and related to severe outcomes (respiratory failure/intensive care unit admission). RESULTS: Elevated admission levels of IL (interleukin)-6, IL-33, IL-8, monocyte chemoattractant protein-1 (MCP-1), interferon-γ-induced protein 10 (IP-10), IL-1ß, and IL-1Ra were associated with severe outcomes during hospitalization. Although no inflammatory markers correlated with VL at baseline, there was a significant correlation between VL and levels of IP-10 and MCP-1 at days 3-5, accompanied by IL-8 and IL-6 at days 7-10. Finally, there was a seemingly additive effect of IP-10, MCP-1, and IL-6 in predicting severe outcomes when combined with high VL at baseline. CONCLUSIONS: An increasing number of inflammatory markers were associated with VL during the first 10 days of hospitalization, and several of these markers were associated with severe outcomes, in particular when combined with elevated VL. Future studies should assess the potential for combining antiviral and immunomodulatory treatment, preferably guided by viral and inflammatory biomarkers, for the selection of high-risk patients.

Nano-Based Approaches in Surface Modifications of Dental Implants: A Literature Review.

Rehabilitation of fully or partially edentulous patients with dental implants represents one of the most frequently used surgical procedures. The work of Branemark, who observed that a piece of titanium embedded in rabbit bone became firmly attached and difficult to remove, introduced the concept of osseointegration and revolutionized modern dentistry. Since then, an ever-growing need for improved implant materials towards enhanced material-tissue integration has emerged. There is a strong belief that nanoscale materials will produce a superior generation of implants with high efficiency, low cost, and high volume. The aim of this review is to explore the contribution of nanomaterials in implantology. A variety of nanomaterials have been proposed as potential candidates for implant surface customization. They can have inherent antibacterial properties, provide enhanced conditions for osseointegration, or act as reservoirs for biomolecules and drugs. Titania nanotubes alone or in combination with biological agents or drugs are used for enhanced tissue integration in dental implants. Regarding immunomodulation and in order to avoid implant rejection, titania nanotubes, graphene, and biopolymers have successfully been utilized, sometimes loaded with anti-inflammatory agents and extracellular vesicles. Peri-implantitis prevention can be achieved through the inherent antibacterial properties of metal nanoparticles and chitosan or hybrid coatings bearing antibiotic substances. For improved corrosion resistance various materials have been explored. However, even though these modifications have shown promising results, future research is necessary to assess their clinical behavior in humans and proceed to widespread commercialization.

Gut-Derived Short-Chain Fatty Acids and Macrophage Modulation: Exploring Therapeutic Potentials in Pulmonary Fungal Infections.

Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, modulate immune cell functions, particularly macrophages. This review explores the potential therapeutic applications of SCFAs in pulmonary fungal infections, a critical concern due to their high mortality rates and antifungal resistance. SCFAs enhance macrophage functions by promoting phagosome-lysosome fusion, increasing reactive oxygen species production, and balancing cytokine responses. Pulmonary fungal infections, caused by pathogens like Aspergillus fumigatus, are prevalent in immunocompromised patients, including those with diabetes, chronic obstructive pulmonary disease, and those on high-dose corticosteroids. SCFAs have shown promise in improving macrophage function in these contexts. However, the application of SCFAs must be balanced against potential side effects, including gut microbiota disruption and metabolic disorders. Further research is needed to optimize SCFA therapy for managing pulmonary fungal infections.

Mangiferin: A natural bioactive immunomodulating glucosylxanthone with potential against cancer and rheumatoid arthritis.

Mangiferin is a naturally occurring glucosylxanthone that has shown promising immunomodulatory effects. It is generally isolated from the leaves, peels, bark, and kernels of Mangifera indica Linn. Mangiferin is like a miraculous natural bioactive molecule that has an immunomodulatory function that makes it a potential therapeutic candidate for the treatment of rheumatoid arthritis (RA) and cancer. The anticancer activity of mangiferin acts by blocking NF-κB, as well as regulating the ß-catenin, EMT, MMP9, MMP2, LDH, ROS, and NO, and also by the activation of macrophages. It has no cytotoxic effect on grown chondrocytes and lowers matrix metalloproteinase levels. Additionally, it has a potent proapoptotic impact on synoviocytes. The precise molecular mechanism of action of mangiferin on RA and malignancies is still unknown. This comprehensive review elaborates on the immunomodulatory effect of mangiferin and its anticancer and anti-RA activity. This also explained the total synthesis of mangiferin and its in vitro and in vivo screening models.

Harnessing Immunomodulatory Polymers for Treatment of Autoimmunity, Allergy, and Transplant Rejection.

Autoimmunity, allergy, and transplant rejection are a collection of chronic diseases that are currently incurable, drastically decrease patient quality of life, and consume considerable health care resources. Underlying each of these diseases is a dysregulated immune system that results in the mounting of an inflammatory response against self or an innocuous antigen. As a consequence, afflicted patients are required to adhere to lifelong regimens of multiple immunomodulatory drugs to control disease and reclaim agency. Unfortunately, current immunomodulatory drugs are associated with a myriad of side effects and adverse events, such as increased risk of cancer and increased risk of serious infection, which negatively impacts patient adherence rates and quality of life. The field of immunoengineering is a new discipline that aims to harness endogenous biological pathways to thwart disease and minimize side effects using novel biomaterial-based strategies. We highlight and discuss polymeric micro/nanoparticles with inherent immunomodulatory properties that are currently under investigation in biomaterial-based therapies for treatment of autoimmunity, allergy, and transplant rejection.

Childhood PFAS exposure and immunotoxicity: a systematic review and meta-analysis of human studies.

BACKGROUND: Exposure to poly- and perfluoroalkyl substances (PFAS) may affect infant and childhood health through immunosuppression. However, the findings of epidemiological literature examining relationships between prenatal/childhood PFAS exposure and vaccine response and infection in humans are still inconclusive. The aim of this review was to examine the effects of PFAS exposure on vaccine antibody response and infection in humans. METHODS: The MEDLINE/Pubmed database was searched for publications until 1 February 2023 to identify human studies on PFAS exposure and human health. Eligible for inclusion studies had to have an epidemiological study design and must have performed logistic regression analyses of gestational or childhood exposure to PFAS against either antibody levels for pediatric vaccines or the occurrence of children's infectious diseases. Information on baseline exposure to PFAS (in ng/mL), the age of PFAS exposure (gestational or in years), and the outcome was measured, potentially leading to multiple exposure-outcome comparisons within each study was collected. Percentage change and standard errors of antibody titers and occurrence of infectious diseases per doubling of PFAS exposure were calculated, and a quality assessment of each study was performed. RESULTS: Seventeen articles were identified matching the inclusion criteria and were included in the meta-analysis. In general, a small decrease in antibody response and some associations between PFAS exposure and childhood infections were observed. CONCLUSIONS: This meta-analysis summarizes the findings of PFAS effects on infant and childhood immune health. The immunosuppression findings for infections yielded suggestive evidence related to PFAS exposure, particularly PFOS, PFOA, PFHxS, and PFNA but moderate to no evidence regarding antibody titer reduction. SYSTEMATIC REVIEW REGISTRATION: The research protocol of this systematic review is registered and accessible at the Open Science Framework ( https://doi.org/10.17605/OSF.IO/5M2VU ).

Clinical outcomes of flavonoids for immunomodulation in inflammatory bowel disease: a narrative review.

Inflammatory bowel disease is a debilitating condition that undergoes a relapsing and remitting course. The pathogenesis of how this disease manifests remains to be elucidated; however, there is growing evidence that a synergism of familial predisposition and epigenetic alterations influenced by environmental factors all contribute to the development of the disease. The role of nutrition in improving the outcomes of the condition has garnered increasing interest, given the greater risks of neoplastic conversion and concerns about inappropriate remission with available pharmacotherapeutic treatments alone. Available reports, often anecdotal, have documented patient relief with employment of various dietary strategies. These have led to curiosity about nutritional assessments and nutrition therapies to ameliorate the morbidity and all-cause mortality of the disease. One group of such nutrition therapies, supported by a compendium of available articles, is flavonoids-although the greater abundance of in vitro experiments with relatively few clinical trials has limited their clinical use. Nonetheless, flavonoids have been shown to be functional foods with immunomodulatory capabilities. This article will thus delve into the role of flavonoids in altering the course of the immune response in inflammatory bowel disease, while assessing their clinical outcomes in human trials.

Exploring the Potential of Glycolytic Modulation in Myeloid-Derived Suppressor Cells for Immunotherapy and Disease Management.

Recent advancements in various technologies have shed light on the critical role of metabolism in immune cells, paving the way for innovative disease treatment strategies through immunometabolism modulation. This review emphasizes the glucose metabolism of myeloid-derived suppressor cells (MDSCs), an emerging pivotal immunosuppressive factor especially within the tumor microenvironment. MDSCs, an immature and heterogeneous myeloid cell population, act as a double-edged sword by exacerbating tumors or mitigating inflammatory diseases through their immune-suppressive functions. Numerous recent studies have centered on glycolysis of MDSC, investigating the regulation of altered glycolytic pathways to manage diseases. However, the specific changes in MDSC glycolysis and their exact functions continue to be areas of ongoing discussion yet. In this paper, we review a range of current findings, including the latest research on the alteration of glycolysis in MDSCs, the consequential functional alterations in these cells, and the outcomes of attempts to modulate MDSC functions by regulating glycolysis. Ultimately, we will provide insights into whether these research efforts could be translated into clinical applications.

Consideration of T-cell profile in the examination of statin efficacy in inflammatory diseases, neurodegeneration, and neurocognitive performance.

Statins are a cornerstone in the medical management of cardiovascular disease, yet their efficacy varies greatly between individuals. In this commentary, we outline evidence for the role of CD4+CD28null T-cell expansion as a critical moderator of the effects of statins in preventing cardiovascular events via the reduction of pathological inflammation. Given this relationship, we argue that T-cell profiles should be considered as a patient characteristic in clinical and pre-clinical studies examining statin efficacy in other age- and inflammation-related pathologies. We discuss the implications this may have for studies of statin use in numerous disease processes - notably, dementia and neurocognitive dysfunction - and the potential for T-cell profiles to be used as a prognosticator for statin efficacy in rheumatoid arthritis, Alzheimer's disease, and multiple sclerosis.

Nanobody Mediated Atrazine Resistance in Plants.

In planta expression of recombinant antibodies has been proposed as a strategy for herbicide resistance but is not well advanced yet. Here, an atrazine nanobody gene fused with a green fluorescent protein tag was transformed to Arabidopsis thaliana, which was confirmed with PCR, ELISA, and immunoblotting. High levels of nanobody accumulation were observed in the nucleus, cytoderm, and cytosol. The nanobody expressed in the plant had similar affinity, sensitivity, and selectivity as that expressed in Escherichia coli. The T3 homozygous line showed resistance in a dose-dependent manner up to 380 g ai/ha of atrazine, which is approximately one-third of the recommended field application rate. This is the first report of utilizing a nanobody in plants against herbicides. The results suggest that utilizing a high-affinity herbicide nanobody gene rather than increasing the expression of nanobodies in plants may be a technically viable approach to acquire commercial herbicide-resistant crops and could be a useful tool to study plant physiology.

Schisandrin A can promote the anti-tumor effect of 5-Fu by reversing the immunosuppressive state of the body in rat.

In this study, based on Walker 256 in vitro experiments, CCK-8 assay, clone formation assay, wound healing assay, and flow cytometry were used to detect cell apoptosis and cell cycle. It was found that schisandrin may have significant anti-tumor effects in vitro by inhibiting TGF-ß/Smad signaling pathway. In addition, in vivo experiments, immunohistochemistry was used to observe the expression of HIF-1α, VEGF and VEGFR-2 in tumor tissues. It was found that schisandrin could significantly improve the immunosuppression induced by 5-Fu and enhance the antitumor effect of 5-Fu. The mechanism may be related to the inhibition of Wnt-1/ß-catenin signaling pathway.

Oral Administration of Limosilactobacillus reuteri KBL346 Ameliorates Influenza Virus A/PR8 Infection in Mouse.

Influenza virus infection is an important public-health concern because of its high transmissibility and potential for severe complications. To mitigate the severity and complications of influenza, probiotics containing Lactobacillus are used and generally recognized as safe. We evaluated the anti-influenza effect of Limosilactobacillus reuteri (L. reuteri) KBL346, isolated from the fecel sample of healthy South Koreans, in mice. BALB/c mice were orally administered live and heat-inactivated L. reuteri KBL346. After infection with influenza virus (A/Puerto Rico/8/34) 0.5 times the 50% lethal dose (LD50), body weight loss was improved and recovery was accelerated. Furthermore, L. reuteri KBL346 improved body weight loss and survival rate of mice infected with 4 times the LD50 of influenza virus. Heat-inactivated L. reuteri KBL346 reduced the viral titer in the lung and the plasma immunoglobulin G level. Expression levels of genes encoding inflammatory cytokines, such as interferon-γ and toll-like receptor 2 (Tlr2), were decreased in the lung tissues of mice administered L. reuteri KBL346. Live and heat-inactivated L. reuteri KBL346 increased the expression level of Adamts4, which promotes recovery after infection, and decreased that of Tlr2. The α-diversity of the gut microbiome was modulated by the administration of L. reuteri KBL346. In addition, the structure of the gut microbial community differed according to the degree of weight loss. L. reuteri KBL346 has the potential to alleviate disease severity and improve histopathological changes in mice infected with influenza A/PR8, suggesting its efficacy as a probiotic against influenza infection.

Indigo Naturalis in Inflammatory Bowel Disease: mechanisms of action and insights from clinical trials.

This study investigates the therapeutic potential of Indigo Naturalis (IN) in treating a Inflammatory Bowel Disease (IBD). The objective is to comprehensively examine the effects and pharmacological mechanisms of IN on IBD, assessing its potential as an novel treatment for IBD. Analysis of 11 selected papers is conducted to understand the effects of IN, focusing on compounds like indirubin, isatin, indigo, and tryptanthrin. This study evaluates their impact on Disease Activity Index (DAI) score, colon length, mucosal damage, and macrophage infiltration in Dextran Sulfate Sodium (DSS)-induced colitis mice. Additionally, It investigate into the anti-inflammatory mechanisms, including Aryl hydrocarbon Receptor (AhR) pathway activation, Nuclear Factor kappa B (NF-κB)/nod-like receptor family pyrin domain containing 3 (NLRP3)/Interleukin 1 beta (IL-1ß) inhibition, and modulation of Toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MYD88)/NF-κB and Mitogen Activated Protein Kinase (MAPK) pathways. Immunomodulatory effects on T helper 17 (Th17)/regulatory T cell (Treg cell) balance and Glycogen synthase kinase-3 beta (GSK3-ß) expression are also explored. Furthermore, the study addresses the role of IN in restoring intestinal microbiota diversity, reducing pathogenic bacteria, and increasing beneficial bacteria. The findings reveal that IN, particularly indirubin and indigo, demonstrates significant improvements in DAI score, colon length, mucosal damage, and macrophage infiltration in DSS-induced colitis mice. The anti-inflammatory effects are attributed to the activation of the AhR pathway, inhibition of inflammatory pathways, and modulation of immune responses. These results exhibit the potential of IN in IBD treatment. Notably, the restoration of intestinal microbiota diversity and balance further supports its efficacy. IN emerges as a promising and effective treatment for IBD, demonstrating anti-inflammatory effects and positive outcomes in preclinical studies. However, potential side effects necessitate further investigation for safe therapeutic development. The study underscores the need for future research to explore a broader range of active ingredients in IN to enhance therapeutic efficacy and safety.