Immune Modulatory Effects Research Articles

Dipeptidyl peptidase IV inhibitors and the risk of mycobacterial pulmonary infections in type 2 diabetes mellitus

BackgroundType 2 diabetes mellitus (DM) is a risk factor for mycobacterial pulmonary infections (MPI), including tuberculosis (TB) and nontuberculous mycobacterial lung disease (NTM-LD). Dipeptidyl peptidase IV inhibitor (DPP4i), a common DM medication, has an immune-modulation effect that raises concerns about developing MPI. However, there is scarce research on the topic. MethodsThis retrospective study was conducted in a tertiary-referral center in Taiwan from 2009 to 2016. Patients with type 2 DM who were receiving any DM medication were enrolled. TB and NTM-LD were defined by microbiological criteria. We analyzed the risk of MPI in DPP4i users using Cox proportional hazard regression with adjusted inverse probability of treatment weighting. ResultsA total of 9963 patients were included. Among them, 3931 were classified as DPP4i users, and 6032 patients were DPP4i nonusers. DPP4i users had no increase in incidences of MPI (604 vs. 768 per 100,000 person-years, p = 0.776), NTM-LD (174 vs. 255 per 100,000 person-years, p = 0.228), and TB (542 vs. 449 per 100,000 person-years, p = 0.663) relative to those of DPP4i nonusers. After adjustment, the adjusted hazard ratios for MPI (aHR: 1.07, 95% CI: 0.79–1.45), TB (aHR: 1.15, 95% CI: 0.81–1.64) and NTM-LD (aHR: 0.85, 95% CI: 0.49–1.47) were not significantly increased relative to those of nonusers. The subgroup analysis also showed that DPP4i use did not increase the risk of MPI in different DM severities and comorbidities. ConclusionsAccording to our large cohort study, DPP4i use is safe for patients with type 2 DM and might not increase the risk of MPI.

Immunostimulatory gene therapy combined with checkpoint blockade reshapes tumor microenvironment and enhances ovarian cancer immunotherapy

Immune evasion has made ovarian cancer notorious for its refractory features, making the development of immunotherapy highly appealing to ovarian cancer treatment. The immune-stimulating cytokine IL-12 exhibits excellent antitumor activities. However, IL-12 can induce IFN-γ release and subsequently upregulate PDL-1 expression on tumor cells. Therefore, the tumor-targeting folate-modified delivery system F-DPC is constructed for concurrent delivery of IL-12 encoding gene and small molecular PDL-1 inhibitor (iPDL-1) to reduce immune escape and boost anti-tumor immunity. The physicochemical characteristics, gene transfection efficiency of the F-DPC nanoparticles in ovarian cancer cells are analyzed. The immune-modulation effects of combination therapy on different immune cells are also studied. Results show that compared with non-folate-modified vector, folate-modified F-DPC can improve the targeting of ovarian cancer and enhance the transfection efficiency of pIL-12. The underlying anti-tumor mechanisms include the regulation of T cells proliferation and activation, NK activation, macrophage polarization and DC maturation. The F-DPC/pIL-12/iPDL-1 complexes have shown outstanding antitumor effects and low toxicity in peritoneal model of ovarian cancer in mice. Taken together, our work provides new insights into ovarian cancer immunotherapy. Novel F-DPC/pIL-12/iPDL-1 complexes are revealed to exert prominent anti-tumor effect by modulating tumor immune microenvironment and preventing immune escape and might be a promising treatment option for ovarian cancer treatment.

Enhanced production of IL-2 from anti-CD3 antibody-stimulated mouse spleen cells by caffeic acid phenethyl ester, a major component of Chinese propolis

ObjectivesWe evaluated the immune-modulatory effects of Chinese propolis (CP) and its major constituent, caffeic acid phenethyl ester (CAPE), on the cytokine production of anti-CD3 antibody-stimulated mouse spleen cells. MethodsMouse spleen cells stimulated by anti-CD3 monoclonal antibody were co–cultured with CP, CAPE, and HC030031, a specific antagonist of the TRPA1 Ca2+-permeable cation channel. Cytokine production was assayed by enzyme-linked immunosorbent assay. Interleukin (IL)-2 mRNA expression was examined by reverse transcription–quantitative polymerase chain reaction. ResultsIn stimulated spleen cells treated with 1/16,000 CP diluent, IL-2 production was markedly enhanced, while IL-4 and IL-10 productions were not significantly affected. In contrast, interferon (IFN)-γ, IL-6, and IL-17 productions were markedly reduced. These effects of CP were reproduced by the CAPE treatment. A time-course observation demonstrated that, compared to control cells, IL-2 mRNA expression and production were significantly enhanced in the spleen cells stimulated by CAPE; however, IL-2 production was markedly delayed compared to that in the untreated control cells. The enhancement of IL-2 production by CAPE was scarcely alleviated by the addition of HC030031. These effects of CAPE upon IL-2 mRNA production were abolished in spleen cells without anti-CD3 antibody stimulation. ConclusionsCAPE is an important regulator of CP for cytokine regulation in anti-CD3 antibody–stimulated spleen cells. The agent specifically reduced IFN-γ, IL-6, and IL-17 and slightly enhanced Th2 cytokine production while significantly enhancing IL-2 production at the transcriptional level.

Engineering Nanotrap Hydrogel for Immune Modulation in Wound Healing.

Imbalanced immune regulation leads to the abnormal wound healing process, e.g., chronic unhealing wound or hypertrophic scar formation. Thus, the attenuation of the overflowing inflammatory factors is a viable approach to maintain the homeostatic immune regulation to facilitate normal wound healing.A versatile telodendrimer (TD) nanotrap (NT) platform is developed for efficient biomolecular protein binding. The conjugation of TD NT in size-exclusive biocompatible hydrogel resin allows for topical application for cytokine scavenging. Fine-tuning the TD NT density/valency in hydrogel resin controls resin swelling, optimizes molecular diffusion, and improves cytokine capture for effective immune modulation. The hydrogel with reduced TD NT density allows for higher protein/cytokine adsorption capacity with faster kinetics, due to the reduced barrierof TD NT nano-assembly. The positively charged TD NT hydrogel exhibits superior removal of negatively charged proinflammatory cytokines from the lipopolysaccharide (LPS, a potent endotoxin) primed immune cell culture medium. The negatively charged TD NT hydrogel removes positively charged anti-inflammatory cytokines efficiently from cell culture medium. TD NT hydrogel effectively constrains the local inflammation induced by subcutaneous LPS injection in mice. These results indicate the great potential applications of the engineered TD NT hydrogel as topical immune modulatory treatments to attenuate local inflammation.

Corrigendum to “Beneficial immune-modulatory effects of the N-163 strain of Aureobasidium pullulans-produced 1,3-1,6 Beta glucans in Duchenne muscular dystrophy: Results of an open-label, prospective, exploratory case-control clinical study” [IBRO Neurosci. Rep. 15 (2023), pp. 90–99

Corrigendum to “Beneficial immune-modulatory effects of the N-163 strain of Aureobasidium pullulans-produced 1,3-1,6 Beta glucans in Duchenne muscular dystrophy: Results of an open-label, prospective, exploratory case-control clinical study” [IBRO Neurosci. Rep. 15 (2023), pp. 90–99

Insights into the Transcriptome of Human Cytomegalovirus: A Comprehensive Review.

Human cytomegalovirus (HCMV) is a widespread pathogen that poses significant risks to immunocompromised individuals. Its genome spans over 230 kbp and potentially encodes over 200 open-reading frames. The HCMV transcriptome consists of various types of RNAs, including messenger RNAs (mRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs), with emerging insights into their biological functions. HCMV mRNAs are involved in crucial viral processes, such as viral replication, transcription, and translation regulation, as well as immune modulation and other effects on host cells. Additionally, four lncRNAs (RNA1.2, RNA2.7, RNA4.9, and RNA5.0) have been identified in HCMV, which play important roles in lytic replication like bypassing acute antiviral responses, promoting cell movement and viral spread, and maintaining HCMV latency. CircRNAs have gained attention for their important and diverse biological functions, including association with different diseases, acting as microRNA sponges, regulating parental gene expression, and serving as translation templates. Remarkably, HCMV encodes miRNAs which play critical roles in silencing human genes and other functions. This review gives an overview of human cytomegalovirus and current research on the HCMV transcriptome during lytic and latent infection.

Changes in peripheral blood immune cell population in thyroid cancer patients treated with lenvatinib

This study evaluated changes in the peripheral blood immune cell population in patients with advanced thyroid cancer receiving lenvatinib treatment to confirm the immune-modulatory effect of lenvatinib. After obtaining informed consent from patients, we prospectively collected 20 ml of whole blood at 2–3 months intervals 2–4 times from each patient; peripheral blood mononuclear cells (PBMCs) were separated, and the Maxpar Direct Immune Profiling Assay was performed. A total of 10 patients were enrolled, and 31 blood samples were obtained. The median age of patients was 65 years, and all patients showed durable responses to the lenvatinib treatment. When we compared the PBMC profiles between the pre-treatment, on-treatment, and off-treatment samples, the peripheral natural killer (NK) cell proportion differed significantly. The proportion of NK cells among total live cells significantly increased from 9.3 ± 4.5 (%) in the pre-treatment samples to 20.8 ± 7.9 (%) in the on-treatment samples (P = 0.009) and decreased to 13.3 ± 3.1 (%) in the off-treatment samples (P = 0.07). There was a significant increase in the peripheral NK cell population with lenvatinib treatment in advanced thyroid cancer patients. This finding confirms the immune-modulatory effect of lenvatinib.

Adjuvant dendritic cell-based immunotherapy after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with malignant peritoneal mesothelioma: a phase II clinical trial

BackgroundMalignant peritoneal mesothelioma (MPM) is an aggressive malignancy with a poor prognosis. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) improves survival outcomes, but recurrence rates remain high. Dendritic cell-based...

MEKiAUTO: A multicenter phase 1 study of combination therapy with the MEK inhibitor, cobimetinib, immune checkpoint blockade, atezolizumab, and the autophagy inhibitor hydroxychloroquine (HCQ) in KRAS-mutated advanced malignancies.

45 Background: Autophagy, a catabolic cell survival process, is upregulated when cancer cells undergo MEK inhibition (MEKi) in preclinical models of pancreas adenocarcinoma (PDAC), and may function as a pathway of resistance. Simultaneous inhibition of the MEK and autophagy pathway in preclinical PDAC models has demonstrated anti-tumor and immune modulating effects. MEKiAUTO evaluated the tolerability and safety of combination cobimetinib, HCQ, and atezolizumab at three dose levels (DL), in advanced KRAS-mutated malignancies. Methods: This multicenter phase I study used the time-to-event continual reassessment method (TITE-CRM) with the primary objective of estimating the maximum tolerated dose (MTD) of the combination of cobimetinib (DL1 and DL2: 40mg; DL3: 60mg PO daily; on days 1-21); HCQ (DL1-DL3: 600mg PO BID), without (DL1) or with (DL2 and DL3) atezolizumab (840mg IV on days 1 and 15) every 28 days, in patients with advanced KRAS-mutated malignancies who had received at least one prior line of therapy (N=18). The secondary objective was to evaluate safety. Exploratory analysis included interrogating the MEK, autophagy, and key molecular pathways. Results: A total of 14 patients with PDAC were enrolled at Columbia University and Brown University between 02/24/20 through 03/15/22. The median age was 58, 57% were female. Of the 10 evaluable patients for dose limiting toxicity ((DLT); >80% drug adherence and ≥4 week of follow-up), 4 experienced a DLT (3 out of 8 at DL1 and 1 out of 2 at DL2). The estimated MTD is dose level 1 with an estimated probability of DLT 0.37. Grade 3 or higher treatment-related adverse events occurred in 7 of 14 (50%) patients with elevation in AST and ALT (14%), acute kidney injury, hypokalemia, anemia, rash, and CPK increase (7% each). One grade 5 multi-organ failure and acute kidney injury occurred at DL1 possibly related to cobimetinib. Clinical benefit was observed in 5 of 14 (36%) patients, all of whom experienced stable disease as best response. The median PFS and OS for overall population was 7.7 weeks (95%CI: 6-NA) and 20.7 weeks (95%CI: 15.6-46.1). Patients with KRASG12R (N=7) had a trend toward longer OS (mOS: 20.9 vs 16.4 weeks) than patients with KRASnon-G12R mutations (N=7). Correlative analysis on paired tumor specimens using single nucleus RNAseq, multiplex immunofluorescence, and pathway analysis will discuss putative mechanisms of resistance. Conclusions: Combination cobimetinib, HCQ and atezolizumab had limited tolerability and efficacy in advanced KRAS-mutated PDAC. Patients with KRASG12R had a trend towards improved OS versus KRASnon-G12R mutations. Correlative analysis for pharmacodynamic and resistance mechanisms will be discussed. Funding: Roche-Genentech. Clinical trial information: NCT04214418 .

JAK1 inhibition with abrocitinib decreases allergen-specific basophil and T-cell activation in pediatric peanut allergy.

JAK1 is a signaling molecule downstream of cytokine receptors, including IL-4 receptor α. Abrocitinib is an oral JAK1 inhibitor; it is a safe and effective US Food and Drug Administration-approved treatment for adults with moderate-to-severe atopic dermatitis. Our objective was to investigate the effect of abrocitinib on basophil activation and T-cell activation in patients with peanut allergy to determine the potential for use of JAK1 inhibitors as a monotherapy or an adjuvant to peanut oral immunotherapy. Basophil activation in whole blood was measured by detection of CD63 expression using flow cytometry. Activation of CD4+ effector and regulatory T cells was determined by the upregulation of CD154 and CD137, respectively, on anti-CD3/CD28- or peanut-stimulated PBMCs. For the quantification of peanut-induced cytokines, PBMCs were stimulated with peanut for 5 days before harvesting supernatant. Abrocitinib decreased the allergen-specific activation of basophils in response to peanut. We showed suppression of effector T-cell activation when stimulated by CD3/CD28 beads in the presence of 10 ng of abrocitinib, whereas activation of regulatory T-cell populations was preserved in the presence of abrocitinib. Abrocitinib induced statistically significant dose-dependent inhibition in IL-5, IL-13, IL-10, IL-9, and TNF-α in the presence of peanut stimulation. These results support our hypothesis that JAK1 inhibition decreases basophil activation and TH2 cytokine signaling, reducing in vitro allergic responses in subjects with peanut allergy. Abrocitinib may be an effective adjunctive immune modulator in conjunction with peanut oral immunotherapy or as a monotherapy for individuals with food allergy.

Immunonutrition in Radical Cystectomy: State of the Art and Perspectives.

Preoperative nutritional status is a pivotal aspect to consider in patients with cancer undergoing radical cystectomy (RC), as those at risk of malnutrition or already malnourished are more prone to post-surgical complications. The loss of muscle mass is a major consequence of cancer-related malnutrition. It is associated with increased risk of hospital readmission, longer hospitalization, and higher mortality. Nowadays, the close relationship between nutritional and immunological aspects under stressful conditions, such as surgery, represents an emerging scientific and clinical issue. Indeed, the synergistic action of reduced food intake and systemic inflammation generates metabolic derangements with tissue catabolism, including skeletal muscle breakdown, which is, in turn, associated with immune system dysfunction. In order to offer an additional immune-nutritional boost to the post-surgical phase, particularly in malnourished patients, nutritional support may include oral nutritional supplements and/or enteral formulas enriched with specific nutrients such as omega-3 fatty acids, arginine, glutamine, and nucleotides, with acknowledged immune-modulating effects. In the present narrative review, we addressed the state of the art of the available scientific literature on the benefit of immunonutrition in patients undergoing RC for cancer and suggest possible future perspectives to be explored. Although the role of immunonutrition was found to be little explored in the context of urologic oncology, the preliminary available data on radical cystectomy, summarized in the present paper, are promising and suggest that it may improve postoperative outcomes through immunomodulation, regardless of nutritional status before surgery.

Effects of Lactiplantibacillus plantarum and Lacticaseibacillus paracasei supplementation on the faecal metabolome in children with coeliac disease autoimmunity: a randomised, double-blinded placebo-controlled clinical trial.

Coeliac disease is a lifelong immune-mediated enteropathy manifested as gluten intolerance in individuals carrying specific human leukocyte antigen (HLA) molecules. Other factors than genetics and gluten intake, however, may play a role in triggering the disease. The gut internal environment is thought to be one of these potential contributing factors, and it can be influenced throughout life. We examine the impact of Lactiplantibacillus plantarum HEAL9 and Lacticaseibacillus paracasei 8700:2 supplementation on the faecal metabolome in genetically predisposed children having tissue transglutaminase autoantibodies, i.e., coeliac disease autoimmunity. Probiotic strains were selected based on their beneficial properties, including mucosal permeability and immune modulation effects. The intervention group (n = 40) and control group (n = 38) took the probiotics or placebo daily for 6 months in a double-blinded randomised trial. Faecal samples were collected at baseline and after 3 and 6 months and analysed using the 1H NMR for metabolome. The incorporation of 16S rRNA sequencing as a supportive dataset complemented the analysis of the metabolome data. During the 6 months of intervention, the stool concentrations of 4-hydroxyphenylacetate increased in the intervention group as compared to controls, whereas concentrations of threonine, valine, leucine, isoleucine, methionine, phenylalanine, aspartate, and fumarate decreased. Additionally, a noteworthy effect on the glycine, serine, and threonine metabolic pathway has been observed. The findings suggest a modest yet significant impact of the probiotics on the faecal metabolome, primarily influencing proteolytic processes in the gut. ClinicalTrials.gov, NCT03176095.

Beneficial immune-modulatory effects of the N-163 strain of Aureobasidium pullulans-produced 1,3-1,6 Beta glucans in Duchenne muscular dystrophy: Results of an open-label, prospective, exploratory case-control clinical study

BackgroundThis exploratory case-control study is to evaluate the effects of supplementation of Aureobasidium pullulans-N-163 strain produced 1,3–1,− 6 beta glucan in young patients with Duchenne muscular dystrophy (DMD). MethodsTwenty-seven male subjects aged 5–19 years with DMD were included, nine in the control arm and 18 in the treatment arm to receive N-163 beta glucan along with conventional therapies for 45 days. While performing the analysis, steroid usage was also taken into consideration, those not administered steroids (Steroid -ve) (Control, n = 5; treatment, n = 9), those administered steroids (Steroid +ve) (Control, n = 4; treatment, n = 9). ResultsIL-6 showed a significant decrease in the treatment groups, especially the N-163 Steroid -ve group. IL-13 decreased in both treatment groups and TGF-β levels showed a significant decrease in the treatment groups, especially the N-163 Steroid –ve group, (p < 0.05). Dystrophin levels increased by up to 32% in the treatment groups compared to the control. Medical research council (MRC) grading showed slight improvement in muscle strength improvement in 12 out of 18 patients (67%) in the treatment group and four out of nine (44%) subjects in the control group. ConclusionSupplementation with the N-163 beta glucan food supplement produced beneficial effects: a significant decrease in inflammation and fibrosis markers, increase in serum dystrophin and slight improvement in muscle strength in DMD subjects over 45 days, thus making this a potential adjunct treatment for DMD after validation. Trial registrationThe study was registered in Clinical trials registry of India, CTRI/2021/05/033346. Registered on 5th May, 2021.

Psidium guajava L.- dichloromethane and ethyl acetate fractions ameliorate striped catfish (Pangasianodon hypophthalmus) status via immune response, inflammatory, and apoptosis pathways.

Psidium guajava L. is known to possess immune-modulatory properties in humans and other mammals. Although the positive effects of P. guajava-based diets on the immunological status have been shown for some fish species, the underlying molecular mechanisms of its protective effects remain to be investigated. The aims of this study were to evaluate the immune-modulatory effects of two guava fractions from dichloromethane (CC) and ethyl acetate (EA) on striped catfish with in vitro and in vivo experiments. Striped catfish head kidney leukocytes were stimulated with 40, 20, 10 and 0μg/ml of each extract fraction, and the immune parameters (ROS, NOS, and lysozyme) were examined at 6 and 24h post stimulation. A final concentration of each fraction at 40, 10 and 0 μg/fish was then intraperitoneally injected into the fish. After 6, 24, and 72h of administration, immune parameters as well as the expression of some cytokines related to innate and adaptive immune responses, inflammation, and apoptosis were measured in the head kidney. Results indicated that the humoral (lysozyme) and cellular (ROS and NOS) immune endpoints were regulated differently by CC and EA fractions depending on dose and time in both, in vitro and in vivo experiments. With regards to the in vivo experiment, the CC fraction of the guava extract could significantly enhance the TLRs-MyD88-NF-κB signaling pathway by upregulating its cytokine genes (tlr1, tlr4, myd88, and traf6), following the upregulation of inflammatory (nfκb, tnf, il1β, and il6) and apoptosis (tp53 and casp8) genes 6h after injection. Moreover, fish treated with both CC and EA fractions significantly enhanced cytokine gene expression including lys and inos at the later time points - 24h or 72h. Our observations suggest that P. guajava fractions modulate the immune, inflammatory, and apoptotic pathways.

A localized hydrogel-mediated chemotherapy causes immunogenic cell death via activation of ceramide-mediated unfolded protein response.

Treatment of triple-negative breast cancer (TNBC) is challenging because of its "COLD" tumor immunosuppressive microenvironment (TIME). Here, we present a hydrogel-mediated localized delivery of a combination of docetaxel (DTX) and carboplatin (CPT) (called DTX-CPT-Gel therapy) that ensured enhanced anticancer effect and tumor regression on multiple murine syngeneic and xenograft tumor models. DTX-CPT-Gel therapy modulated the TIME by an increase of antitumorigenic M1 macrophages, attenuation of myeloid-derived suppressor cells, and increase of granzyme B+CD8+ T cells. DTX-CPT-Gel therapy elevated ceramide levels in tumor tissues that activated the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)-mediated unfolded protein response (UPR). This UPR-mediated activation of apoptotic cell death led to release of damage-associated molecular patterns, thereby activating the immunogenic cell death that could even clear the metastatic tumors. This study provides a promising hydrogel-mediated platform for DTX-CPT therapy that induces tumor regression and effective immune modulation and, therefore, can be explored further for treatment of TNBC.

Vaccination with Toxoplasma lysate antigen or its encapsulated niosomes form immunomodulates adjuvant-induced arthritis through JAK3 downregulation

BackgroundInflammatory autoimmune arthritis like that present in rheumatoid arthritis (RA) is treated by medications with many side effects. This study was a trial to benefit from Toxoplasma immune-modulatory effects on its host to treat arthritis in rat model resembling joints affection of RA. To avoid hazards of infection, Toxoplasma lysate antigen (TLA) was given instead of the whole infection, in addition to giving its encapsulated niosomes form, assuming that it would enhance the effect of TLA alone, to compare effects of both on disease activity with that of prednisolone.MethodsSwiss albino rats were divided into 6 groups: normal control group and the remaining 5 groups were injected by CFA adjuvant to induce arthritis; one of those groups was the untreated model. Each of the other groups received one of the following (TLA, TLA-encapsulated niosomes, prednisolone or niosomes) for comparison of their results. Inflammatory markers measured at the end of the experiment were: interleukin 17 (IL-17), IL-10 and CRP by ELISA technique; histopathological assessment of the biopsied hind paw joints was done and also, Janus kinase 3 (JAK3) expression was assessed by immunohistochemistry.ResultsTLA and TLA-encapsulated niosomes both mitigated the signs of clinical and histopathological arthritis and were having anti-inflammatory effects (decreased CRP, IL-17 and JAK3 expressions, while increased IL-10 levels) with better effects in TLA-encapsulated niosomes-treated RA group, both groups’ results were comparable to prednisolone. Niosomes also gave some anti-inflammatory effects but were mild in comparison to TLA and TLA-encapsulated niosomes.ConclusionVaccination with both TLA and TLA-encapsulated niosomes for the first time in adjuvant-induced arthritis ameliorated the disease through diversion of immune system and JAK3 downregulation. Both vaccinations should be further tested to evaluate the possibility of their introduction for disease treatment and in other autoimmune diseases.

The Impact of Long-Term Macrolide Exposure on the Gut Microbiome and Its Implications for Metabolic Control.

Long-term low-dose macrolide therapy is now widely used in the treatment of chronic respiratory diseases for its immune-modulating effects, although the antimicrobial properties of macrolides can also have collateral impacts on the gut microbiome. We investigated whether such treatment altered intestinal commensal microbiology and whether any such changes affected systemic immune and metabolic regulation. In healthy adults exposed to 4 weeks of low-dose erythromycin or azithromycin, as used clinically, we observed consistent shifts in gut microbiome composition, with a reduction in microbial capacity related to carbohydrate metabolism and short-chain fatty acid biosynthesis. These changes were accompanied by alterations in systemic biomarkers relating to immune (interleukin 5 [IL-5], IL-10, monocyte chemoattractant protein 1 [MCP-1]) and metabolic (serotonin [5-HT], C-peptide) homeostasis. Transplantation of erythromycin-exposed murine microbiota into germ-free mice demonstrated that changes in metabolic homeostasis and gastrointestinal motility, but not systemic immune regulation, resulted from changes in intestinal microbiology caused by macrolide treatment. Our findings highlight the potential for long-term low-dose macrolide therapy to influence host physiology via alteration of the gut microbiome. IMPORTANCE Long-term macrolide therapy is widely used in chronic respiratory diseases although its antibacterial activity can also affect the gut microbiota, a key regulator of host physiology. Macrolide-associated studies on the gut microbiota have been limited to short antibiotic courses and have not examined its consequences for host immune and metabolic regulation. This study revealed that long-term macrolides depleted keystone bacteria and impacted host regulation, mediated directly by macrolide activity or indirectly by alterations to the gut microbiota. Understanding these macrolide-associated mechanisms will contribute to identifying the risk of long-term exposure and highlights the importance of targeted therapy for maintenance of the gut microbiota.

Immune modulatory effects of food supplement products Zeng Jian Heath Tonic and Zhen Yuan Capsule in elderly mice

ABSTRACT Immunosenescence is the degeneration of immunological organs and cells due to aging. Some plants and fungi may have anti-aging benefits through regulating immunosenescence. In this study, mice were fed with two dietary supplement products: Zeng Jian Health Tonic (ZJ) contains extracts from Lentinula edodes, Poria cocos, Tremella fuciformis, cassia seed, Flammulina velutipes, Fructus lycii, chrysanthemum, and mulberry. Zhen Yuan Capsule (ZY) contains extracts from Ganoderma lucidum, Semen cuscutae, Poria cocos, Schisandra chinensis, Codonopsis pilosula, and Atractylodes macrocephala. In addition, the immune organ index, immune cell functions, inflammatory cytokines, and antioxidant enzyme activities were evaluated. The combination of ZJ and ZY could restore the function of lymphocytes and NK cells; decrease the level of pro-inflammatory cytokines including IL-1α, IL-1β, and GM-CSF; increase the level of anti-inflammatory cytokine IL-5; and enhance superoxide dismutase and glutathione peroxidase activities. Therefore, combining ZJ with ZY has anti-aging effects on elderly mice.

The Effects of Mitochondrial Transplantation on Sepsis Depend on the Type of Cell from Which They Are Isolated.

Previously, we have shown that mitochondrial transplantation in the sepsis model has immune modulatory effects. The mitochondrial function could have different characteristics dependent on cell types. Here, we investigated whether the effects of mitochondrial transplantation on the sepsis model could be different depending on the cell type, from which mitochondria were isolated. We isolated mitochondria from L6 muscle cells, clone 9 liver cells and mesenchymal stem cells (MSC). We tested the effects of mitochondrial transplantation using in vitro and in vivo sepsis models. We used the LPS stimulation of THP-1 cell, a monocyte cell line, as an in vitro model. First, we observed changes in mitochondrial function in the mitochondria-transplanted cells. Second, we compared the anti-inflammatory effects of mitochondrial transplantation. Third, we investigated the immune-enhancing effects using the endotoxin tolerance model. In the in vivo polymicrobial fecal slurry sepsis model, we examined the survival and biochemical effects of each type of mitochondrial transplantation. In the in vitro LPS model, mitochondrial transplantation with each cell type improved mitochondrial function, as measured by oxygen consumption. Among the three cell types, L6-mitochondrial transplantation significantly enhanced mitochondrial function. Mitochondrial transplantation with each cell type reduced hyper-inflammation in the acute phase of in vitro LPS model. It also enhanced immune function during the late immune suppression phase, as shown by endotoxin tolerance. These functions were not significantly different between the three cell types of origin for mitochondrial transplantation. However, only L6-mitochondrial transplantation significantly improved survival compared to the control in the polymicrobial intraabdominal sepsis model. The effects of mitochondria transplantation on both in vitro and in vivo sepsis models differed depending on the cell types of origin for mitochondria. L6-mitochondrial transplantation might be more beneficial in the sepsis model.

Immunological evaluation of herbal extracts commonly used for treatment of mental diseases during pregnancy

Nonpsychotic mental diseases (NMDs) affect approximately 15% of pregnant women in the US. Herbal preparations are perceived a safe alternative to placenta-crossing antidepressants or benzodiazepines in the treatment of nonpsychotic mental diseases. But are these drugs really safe for mother and foetus? This question is of great relevance to physicians and patients. Therefore, this study investigates the influence of St. John’s wort, valerian, hops, lavender, and California poppy and their compounds hyperforin and hypericin, protopine, valerenic acid, and valtrate, as well as linalool, on immune modulating effects in vitro. For this purpose a variety of methods was applied to assess the effects on viability and function of human primary lymphocytes. Viability was assessed via spectrometric assessment, flow cytometric detection of cell death markers and comet assay for possible genotoxicity. Functional assessment was conducted via flow cytometric assessment of proliferation, cell cycle and immunophenotyping. For California poppy, lavender, hops, and the compounds protopine and linalool, and valerenic acid, no effect was found on the viability, proliferation, and function of primary human lymphocytes. However, St. John’s wort and valerian inhibited the proliferation of primary human lymphocytes. Hyperforin, hypericin, and valtrate inhibited viability, induced apoptosis, and inhibited cell division. Calculated maximum concentration of compounds in the body fluid, as well as calculated concentrations based on pharmacokinetic data from the literature, were low and supported that the observed effects in vitro would probably have no relevance on patients. In-silico analyses comparing the structure of studied substances with the structure of relevant control substances and known immunosuppressants revealed structural similarities of hyperforin and valerenic acid to the glucocorticoids. Valtrate showed structural similarities to the T cells signaling modulating drugs.