Immunomodulatory Effects Research Articles

Corticosteroids plus metformin versus corticosteroids as front-line treatment for patients with newly diagnosed ITP and pre-existing type 2 diabetes mellitus: A multicentre propensity score-matched study.

Corticosteroids are the standard first-line treatment for primary immune thrombocytopenia (ITP), with a high initial response but unsatisfactory sustained response (SR). Additionally, corticosteroids usually lead to hyperglycaemia especially in patients with pre-existing type 2 diabetes mellitus (T2DM). Besides reducing the blood glucose levels, metformin was found to have immunomodulatory effects. We hereby conducted a multicentre propensity score matching analysis of corticosteroids plus metformin versus corticosteroids for newly diagnosed ITP patients with pre-existing T2DM. After matching at a ratio of 1:1, there were 57 patients in each group. Baseline characteristics, comorbidities and other medications including concurrent hypoglycaemic medications were balanced between the two groups. No statistical difference was observed in the initial response rate at day 14. It was notable that patients in the metformin group had a significantly higher SR rate and longer duration of response compared to the non-metformin group. Metformin inclusion was associated with a higher incidence of stomach upset, which were generally tolerable. Our study provided evidence that the addition of metformin to corticosteroids might be a promising front-line treatment for newly diagnosed ITP patients with pre-existing T2DM.

Aeromonas hydrophila dose and post-immunostimulation period as immunomodulatory effect indicator on Nile tilapia (Oreochromis niloticus)

In fish challenge tests, there is no standardization in the concentration and analysis period of parameters. This study investigates the immunomodulatory and cytotoxic effects of A. hydrophila dose and postimmunostimulation periods on Nile tilapia. Four level of bacterial doses (½, ¼, ⅛, and 0 LD50) were administered, and immune parameters, hematological data, and erythrocyte abnormalities were analyzed at 3, 7, 10, and 14 days post-infection (dpi). The highest respiratory burst, total globulins, and lysozyme activity were detected at 7 dpi. Considering the bacteria doses, the lysozyme activity was higher in the ⅛ LD50 and ¼ LD50 of A. hydrophila. Erythrocytes, hematocrit, hemoglobin, leukocytes, lymphocytes, neutrophils, and monocytes counts remained unchanged. Ten days post-injection, the control group exhibited reduced abnormalities, showing a notable distinction from the ⅛ LD50 and ¼ LD50 treatments, particularly in hooked and notched nuclei abnormalities. Mortality rates were higher in infected groups, peaking at different times with the highest in ½ LD50. For evaluating Nile tilapia immunity post A. hydrophila infection, it is recommended ¼ LD50 dose and blood collection at 7 and 10 dpi for immunological parameters and abnormalities in Nile tilapia erythrocytes, respectively.

Impact of noradrenergic inhibition on neuroinflammation and pathophysiology in mouse models of Alzheimer’s disease

Norepinephrine (NE) modulates cognitive function, arousal, attention, and responses to novelty and stress, and it also regulates neuroinflammation. We previously demonstrated behavioral and immunomodulatory effects of beta-adrenergic pharmacology in mouse models of Alzheimer’s disease (AD). The current studies were designed to block noradrenergic signaling in 5XFAD mice through (1) chemogenetic inhibition of the locus coeruleus (LC), (2) pharmacologic blocking of β-adrenergic receptors, and (3) conditional deletion of β1- or β2-adrenergic receptors (adrb1 or adrb2) in microglia.First, brain-wide AD pathology was mapped in 3D by imaging immunolabeled, cleared 5XFAD brains to assess the overlap between amyloid beta (Aβ) pathology, reactive microglia, and the loss of tyrosine hydroxylase (TH) expression in the catecholaminergic system. To examine the effects of inhibiting the LC NE system in the 5XFAD model, inhibitory (Gi) DREADD receptors were expressed specifically in LC NE neurons. LC NE neurons were chronically inhibited through the subcutaneous pump administration of the DREADD agonist clozapine-N-oxide (CNO). Plasma and brains were collected for assessment of neuroinflammation and pathology. A separate cohort of 5XFAD mice was chronically dosed with the beta-adrenergic antagonist propranolol or vehicle and evaluated for behavior, as well as post-mortem neuroinflammation and pathology. Finally, we used 5XFAD mice with conditional deletion of either adrb1 or adrb2 in microglia to assess neuroinflammation and pathology mediated by β-adrenergic signaling.Using iDISCO+, light sheet fluorescence microscopy, and novel analyses, we detected widespread microgliosis and Aβ pathology, along with modest TH downregulation in fibers across multiple brain regions, in contrast to the spatially limited TH downregulation observed in neurons. Both chemogenetic inhibition of LC adrenergic signaling and pharmacological inhibition of beta-adrenergic receptors potentiated neuroinflammation without altering Aβ pathology. Conditional deletion of adrb1 in microglia did not affect neuroinflammation. Conditional deletion of adrb2 in microglia attenuated inflammation and pathology in females but had no effect in males. Overall, these data support previous observations demonstrating the immunomodulatory effects of beta-adrenergic signaling in the pathophysiology of brain disorders and suggest that adrenergic receptors on cell types other than microglia, such as astrocytes, may mediate some of the disease-modifying effects of β-adrenergic agonists in the brain.

Isolation of bioactive beta-glucans from mycelium of <i>Pleurotus ostreatus</i> mushroom

Background: Beta-glucan, a compound found in higher fungi, possesses significant properties important for the human body, including immunomodulatory effects. Developing efficient extraction technology is crucial to ensure a high yield of beta-glucan component while preserving its bioactive properties. Context and purpose of this study: This study aimed to evaluate the extraction efficiency of beta-glucans from Pleurotus ostreatus mycelium powder using microwave-assisted extraction and to compare its performance with traditional extraction methods—specifically water and ethyl alcohol-based extractions. Objective: The aim of this study is to increase the yield of the aqueous extract of beta-glucan from the mycelium of the fungus Pleurotus ostreatus, while ensuring its biological activity is preserved for subsequent use in the fortifying food products. To achieve this, various extraction methods were employed. Results: Traditional methods of beta-glucan extraction, including water and ethyl alcohol-based processes, yielded the largest amount of beta-glucan of 1.45 ± 0.02 g of beta-glucan. The stimulation index, a measure of beta-glucans on the human phagocytosis system, reached 1.28 under optimal conditions — double treatment with ethanol followed by a double extraction with water, each extraction lasting three hours. When extracting beta-glucan using microwave radiation, 2.97 g of beta-glucan was obtained—2.05 times greater than traditional methods. The simulation index also improved by 13%, reaching 1.47% while reducing the extraction time. Conclusions: Based on the conducted research, it has been found that the extraction of beta-glucan from the mycelium of the Pleurotus ostreatus fungus is advisable to carry out using microwave processing, which significantly reduces the extraction time while maintaining the biological activity of beta-glucan. Keywords: Basidiomycetes, Pleurotus ostreatus, beta-glucan, water extraction, ethyl alcohol extraction, microwave radiation, immunomodulatory properties.

Dietary Modulation of the Immune System

Recent insights into the influence of nutrition on immune system components have driven the development of dietary strategies targeting the prevention and management of major metabolic-inflammatory diseases. This review summarizes the bidirectional relationship between nutrition and immunocompetence, beginning with an overview of immune system components and their functions. It examines the effects of nutritional status, dietary patterns, and food bioactives on systemic inflammation, immune cell populations, and lymphoid tissues, as well as their associations with infectious and chronic disease pathogenesis. The mechanisms by which key nutrients influence immune constituents are delineated, focusing on vitamins A, D, E, C, and B, as well as minerals including zinc, iron, and selenium. Also highlighted are the immunomodulatory effects of polyunsaturated fatty acids as well as bioactive phenolic compounds and probiotics, given their expanding relevance. Each section addresses the implications of nutritional and nutraceutical interventions involving these nutrients within the broader context of major infectious, metabolic, and inflammatory diseases. This review further underscores that, while targeted nutrient supplementation can effectively restore immune function to optimal levels, caution is necessary in certain cases, as it may increase morbidity in specific diseases. In other instances, dietary counseling should be integrated to ensure that therapeutic goals are achieved safely and effectively.

Synergistic Enhancement of Antibacterial and Osteo-Immunomodulatory Activities of Titanium Implants via Dual-Responsive Multifunctional Surfaces.

Bone implant-associated infections and inflammations, primarily caused by bacteria colonization, frequently result in unsuccessful procedures and pose significant health risks to patients. To mitigate these challenges, the development of engineered implants with spatiotemporal regulation capabilities, designed to inhibit bacterial survival and modulate immune responses in the early stage, while promoting bone defect healing in the late stage is proposed. The implants are functionalized with ε-poly-l-lysine-phenylboronic acid (PP) via dynamic boronic ester bonds, which facilitate its release through a reactive oxygen species (ROS) and pH-responsive strategy, thereby establishing an antibacterial microenvironment on and around the implants. Additionally, the dynamic metal coordination interaction facilitates the loading and sustained release of Sr2+ under an acidic environment, providing immunomodulatory and osteogenic effects. The ROS/pH-responsive feature, coupled with the implant-bone tissue integration process, affords precise spatiotemporal regulation of the Ti-TA-Sr-PP implants. This strategy represents a promising approach for the preparation of advanced bone implants.

The current state of research on the pharmacological properties of melanins and the prospects for their use in medicine

Introduction. This article discusses the basic physico-chemical properties of melanins, their biosynthesis, and the potential for their use in medicine. As a result of the review, based on a number of scientific studies, it was revealed that melanins are characterized by a wide range of biological activity. They have photoprotective, radioprotective, immunomodulatory, stress-protective, antioxidant, detoxification and anti-inflammatory effects. The presented information indicates the promising use of melanins in medical practice in the treatment of diseases of the immune, central nervous, cardiovascular systems, and some oncological diseases. The purpose of the study was to review the Russian and foreign literature on melanins, their biosynthesis, functional properties and prospects for their use in medicine. Methods. content analysis of scientific publications to identify the structure, biosynthesis, and biopharmacological properties of melanins in the databases: CyberLeninka, eLibrary, PubMed, Article, SAGE Premier, Scopus over the past 12 years (2013–2024); comparative analysis of various properties of melanins based on current scientific literature data Conclusion. The information obtained and the justification of the prospects for the use of melanins in clinical practice allow us to speak about the relevance of the development of formulations and technology for the production of drugs based on it, including in the form of combined drugs with a multifunctional effect in various dosage forms. Melanin nanoparticles are promising as a multifunctional nanoplatform for use in oncology, cardiology and restorative medicine.

TLS and immune cell profiling: immunomodulatory effects of immunochemotherapy on tumor microenvironment in resectable stage III NSCLC

BackgroundThe use of programmed death-1 (PD-1) inhibitors in the neoadjuvant setting for patients with resectable stage III NSCLC has revolutionized this field in recent years. However, there is still 40%-60% of patients do not benefit from this approach. The complex interactions between immune cell subtypes and tertiary lymphoid structures (TLSs) within the tumor microenvironment (TME) may influence prognosis and the response to immunochemotherapy. This study aims to assess the relationship between immune cells subtypes and TLSs to better understand their impact on immunotherapy response.MethodsThis study initially compared the tertiary lymphoid structures (TLSs) density among patients who underwent immunochemotherapy, chemotherapy and upfront surgery using 123 tumor samples from stage-matched patients. Multiplex immunohistochemistry (mIHC) was employed to analyze the spatial distribution of PD-L1+CD11c+ cells and PD1+CD8+ T cells within TLSs. Cytometry by time-of-flight (CyTOF) was used to assess immune cell dynamics in paired biopsy and resection specimens from six patients who underwent immunochemotherapy. Key immune cells were validated in newly collected samples using flow cytometry, mIHC, and in vitro CAR-T cells model.ResultsPatients who underwent neoadjuvant chemotherapy or immunochemotherapy exhibited increased TLSs compared to those who opted for upfront surgery. The TLS area-to-tumor area ratio distinguished pCR+MPR and NR patients in the immunochemotherapy group. Spatial analysis revealed variations in the distance between PD-L1+CD11c+ cells and PD1+CD8+ T cells within TLSs in the immunochemotherapy group. CyTOF analysis revealed an increase in the frequency of key immune cells (CCR7+CD127+CD69+CD4+ and CD38+CD8+ cells) following combined therapy. Treatment responders exhibited an increase in CCR7+CD4+ T cells, whereas CD38+CD8+ T cells were associated with compromised treatment effectiveness.ConclusionsImmunochemotherapy and chemotherapy increase TLSs and granzyme B+ CD8+ T cells in tumors. The TLS area-to-tumor ratio distinguishes responders from non-responders, with PD-L1+ dendritic cells near CD8+PD-1+ T cells linked to efficacy, suggesting that PD-1 inhibitors disrupt harmful interactions. Post-immunochemotherapy, CD8+ T cells increase, but CD38+CD8+ T cells show reduced functionality. These findings highlight the complex immune dynamics and their implications for NSCLC treatment.

Efficacy of combining aspirin with hydroxychloroquine in pregnancies at high risk for pre-eclampsia: a prospective, multicentre, open-label, single-arm clinical trial, investigator-initiated study (HUGS study)

IntroductionThe use of hydroxychloroquine (HCQ) during pregnancies complicated by systemic lupus erythematosus or refractory antiphospholipid antibody syndrome has demonstrated a significant ability to prevent pre-eclampsia (PE). As such, the potential...

Non-Targeted Metabolomics Analysis Reveals Metabolite Profiles Change During Whey Fermentation with Kluyveromyces marxianus

Background: Whey fermentation could produce bioactive substances with immunomodulatory effects, metabolic syndrome modulation, and antioxidant properties, thereby imparting functional characteristics to products and facilitating the development of novel foods with health-promoting potential. Methods: A non-targeted metabolomics approach using liquid chromatography–mass spectrometry (LC-MS) was employed to investigate changes in the metabolite profiles of whey fermented by Kluyveromyces marxianus strain KM812 over varying fermentation durations. Results: The findings demonstrated a progressive enrichment of metabolites over time. A total of 151 differential metabolites were identified and categorized primarily into amino acids, peptides, and analogues, fatty acids and conjugates, and carbohydrates and conjugates, as well as benzoic acids and derivatives. The highest relative content of whey metabolites was observed at 48 h of fermentation, with a cumulative increase of 1.45-fold, 1.49-fold, 3.39-fold, and 1.24-fold for peptides and amino acids, peptides, and analogues, fatty acids and conjugates, and carbohydrates and conjugates, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed associations with 23 specific metabolites and delineated 9 metabolic pathways, predominantly involved in amino acid and lipid metabolism. Conclusions: Based on the above, KM812 could effectively degrade macromolecular substances in whey into small molecules such as L-isoleucine, ornithine, betaine, α-linolenic acid, and palmitoleic acid, thereby influencing the nutritional and functional properties of whey. In-depth analysis of the metabolic products in KM812-fermented whey could provide a theoretical basis for the development of functional foods derived from small molecules in the future.

Immunomodulatory Effects of Andrographis paniculata Leaf Extract in Cyclophosphamide-induced Immunosuppressed Mice

Background Cyclophosphamide is one of the most extensively used chemotherapeutic drugs and is employed to treat several malignancies. Cyclophosphamide often comes with several unpleasant side effects. The primary negative consequence of cyclophosphamide in clinical chemotherapy is immunosuppression, which can lead to life-threatening complications. Objectives: The present work was dedicated to exploring the therapeutic effects of Andrographis paniculata against cyclophosphamide-induced immunosuppression in mice. Materials and Methods The BALB/c mice were treated with 80 mg/kg of cyclophosphamide to achieve immunosuppression and treated with 250 and 500 mg/kg of A. paniculata extract. 10 mg/kg of levamisole was used as a standard drug. After the completion of the treatments, the body weights of the experimental animals were measured. The immune organs (spleen and thymus) were determined by standard methods. The levels of blood components were studied using an automated hematological analyzer. The macrophage phagocytic index, humoral response, and delayed immune response were studied by standard methods. The histopathological analysis was done on the heart, spleen, and thymus. Results The treatment with 250 and 500 mg/kg of A. paniculata extract substantially increased the body weight and elevated the immune organ index in the immunosuppressed mice. The changes in the levels of hematological parameters were successfully modulated by A. paniculata. The levels of macrophage phagocytic index and delayed and humoral immune responses were boosted by the A. paniculata extract treatment in the immunosuppressed mice. The outcomes of histopathological analysis exhibited that the A. paniculata extract attenuated the cyclophosphamide-induced damage to the heart, thymus, and spleen tissues. Conclusion The findings of the current work validate the immunomodulatory properties of A. paniculata extract in cyclophosphamide-induced immunosuppressed mice. Hence, it was clear that A. paniculata can be a talented immunomodulatory agent to treat immunological complications.

Seaweed-Derived Bioactive Compounds: Potent Modulators in Breast Cancer Therapy.

Cancer remains a major global health concern, with breast cancer being particularly challenging. To address this, new therapeutic strategies are being explored, including natural alternatives. Seaweeds, rich in bioactive compounds, have gained attention for their therapeutic potential. Traditionally valued for their nutritional content, seaweed-derived compounds such as polysaccharides, polyphenols, sterols, vitamins, minerals, and carotenoids have shown anti-cancer properties. These compounds can modulate key cellular processes like apoptosis, angiogenesis, and inflammation-crucial in cancer progression. Their antioxidant, anti-inflammatory, and immunomodulatory effects make them promising candidates for complementary cancer therapies. Key bioactive components like fucoidans, laminarins, phlorotannins, and carotenoids exhibit anti-proliferative, pro-apoptotic, anti-angiogenic, and anti-metastatic properties. Recent studies focus on the ability of these compounds to induce apoptosis in cancer cells. This review highlights the chemical constituents of various seaweed species with anti-tumor activity, their mechanisms of action, and the potential for integration into cancer treatments. It also addresses challenges in clinical applications and outlines future research directions for leveraging these marine resources in breast cancer therapy.

Effects of 1H-1,2,3-Triazole Derivatives of 3-O-Acetyl-11-Keto-Beta-Boswellic Acid from Boswellia sacra Resin on T-Cell Proliferation and Activation

Background: 3-O-acetyl-11-keto-β-boswellic acid (β-AKBA), a triterpene natural product, is one of the main natural products of Boswellia sacra resin (BSR) and has reported biological and immunomodulatory effects. 1H-1,2,3-triazole derivatives of β-AKBA (named 6a–6d) were synthesized from β-AKBA. The 1H-1,2,3-triazole compounds are also known to have a wide range of biological and pharmacological properties as demonstrated by in vitro and in vivo studies. This study aimed to investigate the effects of these 1H-1,2,3-triazole derivatives of β-AKBA on human T-cell proliferation and activation. Methods: PBMCs isolated from healthy donors were activated by anti-CD3/CD28 monoclonal antibodies in the presence of β-AKBA (1) or 1H-1,2,3-triazole derivatives of β-AKBA or DMSO controls. Results: We found that similar to the parent compound β-AKBA (1), derivatives 6a, 6b, and 6d significantly inhibited T-cell expansion/proliferation and reduced the levels of CD25 activation marker on CD4+ and CD8+ T cells without exerting significant cytotoxic effects on T-cell viability at a concentration of 25 µM. However, compound 6c further inhibited T-cell expansion/proliferation and CD25 expression, but had a significant cytotoxic effect on cell viability at similar concentrations of 25 µM. Conclusions: These findings demonstrate the immunoinhibitory effects of β-AKBA (1) and its corresponding triazole derivatives on T-cell proliferation and activation, highlighting the promising therapeutic potential of these compounds in T-cell-mediated diseases.

Melatonin as a multifunctional modulator: emerging insights into its role in health, reproductive efficiency, and productive performance in livestock

Melatonin, a pleiotropic hormone plays a vital role in enhancing livestock performance not only by regulating circadian rhythms but also by exhibiting antioxidant, immunomodulatory, and metabolic regulatory effects that collectively improve resilience, fertility, and productivity. Melatonin’s synthesis is predominantly influenced by light exposure, with increased production in darkness; however, factors such as diet and health status further modulate its levels. By helping animals adapt to environmental stressors, melatonin boosts immune responses, mitigates chronic illnesses, and optimizes production efficiency. Its regulatory influence extends to the hypothalamic-pituitary-gonadal (HPG) axis, enhancing hormone secretion, synchronizing estrous cycles, and improving embryo viability. This results in improved reproductive outcomes through the protection of gametes, increased sperm motility, and enhanced oocyte quality, all of which benefit the fertilization process. Additionally, melatonin positively impacts productive performance, promoting muscle growth, development, and optimizing milk yield and composition through its interaction with metabolic and endocrine systems. As ongoing research continues to uncover its broader physiological effects, melatonin supplementation emerges as a promising approach to improving livestock welfare, productivity, and sustainability in modern animal husbandry.

Immunomodulatory Effects of Nellikai Thenural Against Thiamethoxam-Induced Toxicity in Carassius auratus

The accumulation of pesticides in aquatic ecosystems poses significant risks to non-target organisms, particularly fish populations. The study evaluated the protective effects of Nellikai Thenural, a traditional Siddha formulation containing Emblica officinalis and honey, against thiamethoxam-induced toxicity in Carassius auratus (goldfish). The experimental design comprised four groups: control, Nellikai Thenural-treated (733 μg), thiamethoxam-exposed (114.84 mg/L), and co-administered (thiamethoxam + Nellikai Thenural) groups. The LC50 value of Nellikai Thenural was determined at 916 μg/ml/kg body weight through brine shrimp lethality assay. Hematological parameters revealed significant alterations in thiamethoxam-exposed fish, with decreased RBC count, hemoglobin levels, and WBC count. The administration of Nellikai Thenural effectively restored these parameters toward normal levels. Biochemical markers, including plasma proteins, immunoglobulins, and tissue-specific enzymes (ALP, ACP, AST), showed marked improvement in the co-administered group compared to thiamethoxam-exposed fish. Behavioral observations indicated reduced stress responses and improved swimming patterns in fish treated with Nellikai Thenural. The findings demonstrate the potential of Nellikai Thenural as a natural immunostimulant and protective agent against pesticide-induced toxicity in aquatic organisms.

Immunomodulatory properties of polysaccharide extract samples from Cyanobacterium sp. Rippka B-1200

Cyanobacteria are most abundant in aquatic systems and can grow in freshwater, saline or brackish water, and cold/hot springs. Cyanobacteria have attracted considerable research attention in the last decade as a potential source of numerous biological products in large quantities, such as biofuels, pigments, polyunsaturated fatty acids, nutraceuticals, enzymes, and polysaccharides. Unlike most plant and fungal polysaccharides, the chemical composition, immunomodulatory activity, and molecular mechanisms of action of Cyanobacterium sp. Rippka B-1200 polysaccharides have been studied much less. The complexity of their primary structure due to the high variability of monosaccharides, their diverse bonds, the presence of substituents and high viscosity made detailed structural studies of cyanobacterial polysaccharides rare, which determines the need for analysis of cyanobacteria biomass components to identify active metabolites with promising biological activity. The aim of this study was to investigate the immunomodulatory properties of polysaccharides from Cyanobacterium sp. Rippka B-1200. Pharmacological and nutraceutical value of Cyanobacterium sp. Rippka B-1200 has been set, defining our study’s scientific novelty. As a result, the molecular weight of immunoactive polysaccharide (6.0–8.0 kDa) was determined. The analysis shows that endopolysaccharide samples at a concentration of 300 mg/kg showed no significant immunomodulatory effect (1.60 ± 0.15 mg/g), and the thymus mass index of animals in the experimental group was comparable to that of the control group in which animals were immunosuppressed with cyclophosphamide (1.15 ± 0.24 mg/g). When exopolysaccharide samples were used at a concentration of 600 mg/kg, the thymus mass index of animals in the experimental group (3.60 ± 0.32 mg/g) was statistically comparable to that of the control group (without polysaccharide) in which immunosuppression was not induced (thymus index was 3.70 ± 0.25 mg/g). It was found that endopolysaccharide samples at a concentration of 600 mg/kg also exhibited high immunomodulatory activity. When Cyanobacterium sp. Rippka B-1200 endopolysaccharide samples were used, no internal organ changes were observed in experimental animals after immunosuppression. The empirical results presented in the study may find application in the development of both pharmaceutical and cosmetic products.

Heterologous Biosynthesis of Taxifolin in Yarrowia lipolytica: Metabolic Engineering and Genome-Scale Metabolic Modeling.

Taxifolin, also known as dihydroquercetin (DHQ), is a flavonoid recognized for its potent antioxidant properties and a wide range of biological activities, including anti-tumor, antiviral, and immunomodulatory effects. Conventional extraction and chemical synthesis methods for taxifolin are often limited by low yields and associated environmental concerns. In this study, we investigated the heterologous biosynthesis of taxifolin in Yarrowia lipolytica through a combination of metabolic engineering and genome-scale metabolic modeling (GSM), complemented by flux balance analysis (FBA). We engineered Yarrowia lipolytica by introducing key biosynthetic genes and successfully synthesized taxifolin using naringenin (NAR) as a substrate, chosen for its low cost. Fermentation experiments demonstrated an optimal taxifolin yield of 10% at a substrate concentration of 200mg/L naringenin, with a maximum yield of 26.4mg/L taxifolin at 1g/L naringenin. To further enhance production, we applied a marker-free Cre-loxP-based gene integration method, allowing stable genomic integration of key genes, which increased taxifolin yield to 34.9mg/L at 1g/L naringenin. Additionally, intermediate metabolites eriodictyol (ERI) and dihydrokaempferol (DHK) accumulated to concentrations of 89.2mg/L and 21.7mg/L, respectively. Furthermore, we integrated metabolic data into a GSM and applied FBA to optimize the taxifolin biosynthetic pathway. Through Pareto frontier analysis, sensitivity analysis, flux variability analysis, and single gene deletion simulations, we identified key genetic modifications that significantly enhanced taxifolin yield. Overexpression of GND1 and IDP2 increased yields by 94% and 155%, respectively, while knockout of LIP2 led to a 46% increase. Using tri-baffled shake flasks to improve oxygen supply resulted in a 120% yield increase, whereas YPG medium decreased yield by 59%, validating our model's accuracy. To ensure stable and efficient gene expression, we integrated multi-copy constructs into the ribosomal DNA (rDNA) locus of Yarrowia lipolytica, doubling taxifolin production. These results demonstrate the effectiveness of GSM and FBA in addressing bottlenecks in microbial taxifolin biosynthesis and provide a basis for future optimization and large-scale production.

LC–MS-based quantitation of proteomic changes induced by Norcantharidin in MTB-Treated macrophages

Tuberculosis drug resistance contributes to the spread of tuberculosis. Immunotherapy is an effective strategy for treating tuberculosis, with the regulation of macrophage-mediated anti-tuberculosis immunity being crucial. Norcantharidin (NCTD), a drug used in tumor immunotherapy, has significant immunomodulatory effects. Thus, NCTD may have an anti-tuberculosis role by regulating immunity. Understanding how NCTD affects the proteome of Mtb-infected macrophages can provide valuable insights into potential treatments. This study aimed to investigate the impact of NCTD (10 μg/mL) on the proteome of macrophages infected with Mtb H37Ra using liquid chromatography-tandem mass spectrometry (LC–MS/MS) analysis. A total of 69 differentially regulated proteins (DRPs) were identified, with 28 up-regulated and 41 down-regulated in the NCTD-treated group. Validation of six DRPs (CLTCL1, VAV1, SP1, TRIM24, MYO1G, and WDR70) by Western blot analysis confirmed the accuracy of the LC–MS/MS method used in this study. NCTD modulates various protein expressions involved in chromatin-modifying enzymes, RHO GTPases activating PAKs, Fc gamma R-mediated phagocytosis, T cell receptor signaling pathway, and antigen processing and presentation. Overall, the research provides new insights into the effects of NCTD on the proteome of Mtb-infected macrophages. The identified changes highlight potential targets for future therapeutic interventions aimed at enhancing host immunity against Mtb infection or developing new anti-TB drugs based on these findings.

Perioperative management of patients receiving glucocorticoids in rheumatology

Glucocorticoids are a cornerstone in the management of rheumatic diseases due to their potent anti-inflammatory and immunomodulatory effects. However, their perioperative use presents distinct challenges, including an elevated risk of infection, impaired wound healing, and the potential for glucocorticoid-induced adrenal insufficiency (GI-AI). This review examines the perioperative implications of glucocorticoid therapy, with a focus on infection risk, adrenal insufficiency, and recommendations from clinical practice guidelines. Evidence indicates a correlation between glucocorticoid use and increased perioperative complications, although the efficacy of dose reduction strategies in mitigating these risks remains uncertain. GI-AI, a common complication of prolonged glucocorticoid use, necessitates careful perioperative management to prevent adrenal crises. Guidelines from British, American, and German societies propose slightly differing approaches, albeit with low levels of evidence, emphasizing the importance of individualized patient care.

Enhancing cancer therapy: advanced nanovehicle delivery systems for oridonin.

Oridonin (ORI), an ent-kaurane diterpenoid derived from Rabdosia rubescens (Hemsl.) H.Hara, serves as the primary bioactive component of this plant. It demonstrates a broad spectrum of therapeutic activities, including moderate to potent anticancer properties, alongside anti-inflammatory, antibacterial, antifibrotic, immunomodulatory, and neuromodulatory effects, thus influencing diverse biological processes. However, its clinical potential is significantly constrained by poor aqueous solubility and limited bioavailability. In alignment with the approach of developing drug candidates from natural compounds, various strategies, such as structural modification and nanocarrier systems, have been employed to address these challenges. This review provides an overview of ORI-based nano-delivery systems, emphasizing their potential to improve the clinical applicability of oridonin in oncology. Although some progress has been made in advancing ORI nano-delivery research, it remains insufficient for clinical implementation, necessitating further investigation.