Number Of TH Research Articles

Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the immune system maternal-fetal interface during palatal development

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is an important environmental pollutant that disturbs the immune balance of the maternal-fetal interface (MFI) and is also a common environmental factor for the formation of cleft palate (CP). Therefore, the purpose is to investigate whether TCDD can cause CP by disrupting the immune balance of the maternal-fetal interface. Fifteen C57BL/6J mice were randomly assigned to three groups: control group, TCDD group, and TCDD plus Freund’s complete adjuvant (FCA) (TCDD + FCA) group. Peripheral blood, placentas, and palatal tissues were collected for H&E, flow cytometry, and ELISA. In the TCDD group, the placental diameter, the number of placental labyrinth vessels, and the area of sponge layer cells were all significantly reduced. At embryonic day (E) 17.0, there was a significant decrease in T-helper 1 (Th1) and Th2 cells in the peripheral blood of pregnant mice. Additionally, the levels of interferon-γ (IFN-γ) and interleukin-4 (IL-4), particularly IL-4, were significantly decreased. However, after treatment with FCA, the distance between the palatal shelves was reduced, and the placental weight, the number of labyrinth vessels, and the area of the cavernous cells in the placenta also increased. The number of Th1 and Th2 cells significantly increased, returning to the levels observed in the control group, with a more pronounced increase in the number of Th2 cells. In conclusion, TCDD may induce CP by disrupting the homeostasis of the MFI. The precise mechanisms by which TCDD impacts the immune system at the MFI require further investigation.2,3,7,8-四氯二苯并-对二恶英 （TCDD） 是一种重要的环境污染物，会扰乱母胎界面 （MFI） 的免疫平衡，也是形成腭裂 （CP） 的常见环境因素。因此，目的是研究 TCDD 是否可以通过破坏母胎界面的免疫平衡来引起 CP。将 15 只 C57BL/6J 小鼠随机分为 3 组：对照组、TCDD 组和 TCDD 加弗氏完全佐剂 （FCA） （TCDD + FCA） 组。收集外周血、胎盘和腭组织用于 H&E、流式细胞术和 ELISA。TCDD 组胎盘直径、胎盘迷路血管数量和海绵层细胞面积均显著减少。在胚胎第 17.0 天 （E） 时，妊娠小鼠外周血中的 T 辅助细胞 1 （Th1） 和 Th2 细胞显著减少。此外，干扰素-γ （IFN-γ） 和白细胞介素-4 （IL-4），特别是 IL-4 的水平显着降低。然而，用 FCA 处理后，腭架之间的距离减小，胎盘重量、迷路血管的数量和胎盘中海绵状细胞的面积也增加。Th1 和 Th2 细胞的数量显著增加，恢复到对照组观察到的水平，Th2 细胞的数量增加更明显。总之，TCDD 可能通过破坏 MFI 的稳态来诱导 CP。TCDD 影响 MFI 免疫系统的确切机制需要进一步研究。

Heat shock protein 70 promotes the progression of type 2 diabetic nephropathy by inhibiting T-cell immunoglobulin and mucin domain-3 and thereby promoting Th17/Treg imbalance.

Diabetic nephropathy (DN) is the most common complication of diabetes mellitus. We aimed to investigate the role of regulatory T cells (Tregs) and helper T cells 17 (Th17) in the development and progression of DN. A mouse type 2 diabetic nephropathy (T2DN) model was established. Immunohistochemistry was used to detect the expression of HSP70 and Tim-3 in mouse kidney tissues, and western blotting was used to detect the expression levels of HSP70 and Tim-3. PAS staining and Masson's trichrome staining were used to detect the degree of kidney injury. Flow cytometry was used to detect the number of Th17 and Treg cells in blood and kidney tissues. The expression levels of interleukin 17 (IL-17) and interleukin 10 (IL-10) in the serum were measured via ELISA. The expression of HSP70 was significantly increased while the expression of Tim-3 was significantly decreased in the kidneys of mice in the T2DN group compared with those in the control (NC) group. Additionally, the inhibition of HSP70 upregulated the expression of Tim-3 in T2DN mice. The Th17/Treg ratio was significantly greater in the blood and kidneys of the mice in the T2DN group than in those of the NC group, the expression of serum IL-17 was increased, and the expression of IL-10 was decreased. Increased HSP70 inhibits Tim-3 expression in T2DN mouse kidney tissues, and subsequently causes a Th17/Treg imbalance and an inflammatory response, ultimately leading to kidney injury. The inhibition of HSP70 may alleviate the progression of T2DN.

AdipoRon improves mitochondrial homeostasis and protects dopaminergic neurons through activation of the AMPK signaling pathway in the 6-OHDA-lesioned rats

The progressive decline of dopaminergic neurons in Parkinson's disease (PD) has been linked to an imbalance in energy and the failure of mitochondrial function. AMP-activated protein kinase (AMPK), the major intracellular energy sensor, regulates energy balance, and damage to nigral dopaminergic neurons induced by 6-hydroxydopamine (6-OHDA) is exacerbated in the absence of AMPK activity. This study aimed to examine the potential therapeutic advantages of AdipoRon, an AMPK activator, on motor function and mitochondrial homeostasis in a 6-OHDA-induced PD model. Male Wistar rats were subjected to unilateral injection of 6-OHDA (10 μg) into the left medial forebrain bundle at two points, and after 7 days, they were treated with intranasal AdipoRon (0.1, 1, and 10 μg) or Levodopa (10 mg/kg, p. o.) for 21 successive days. Following the last treatment day, motor behavior was evaluated through the Murprogo's test, bar test, beam walking test, and apomorphine-induced rotation test. After euthanasia, the left substantia nigra (SN) was separated for evaluation of ATP, mitochondrial membrane potential (MMP), and protein expressions of AMPK, p-AMPK, and mitochondrial dynamics markers (Mfn-2 and Drp-1). Moreover, the number of tyrosine hydroxylase-positive (TH+) cells was quantified in the left substantia nigra. Intranasal AdipoRon effectively reversed muscle rigidity, akinesia, bradykinesia, and rotation caused by 6-OHDA. Moreover, AdipoRon increased the phospho-AMPK/AMPK ratio, mitigated mitochondrial dysfunction, and improved mitochondrial dynamics in the SN. Furthermore, AdipoRon increased the number of TH+ cells in the SN of PD animals. These findings suggest that AdipoRon could protect dopaminergic neurons by activating the AMPK pathway and improving mitochondrial dysfunction.

Abatacept inhibits Th17 differentiation and mitigates α-synuclein-induced dopaminergic dysfunction in mice.

Parkinson's disease (PD) is a multifaceted disease characterized by degeneration of nigrostriatal dopaminergic neurons, which results in motor and non-motor dysfunctions. Accumulation of α-synuclein (αSYN) in Lewy bodies is a key pathological feature of PD. Although the exact cause of PD remains unknown, accumulating evidence suggests that brain infiltration of T cells plays a critical role in the pathogenesis of disease, contributing to neuroinflammation and dopaminergic neurodegeneration. Here, we used a mouse model of brain-infused aggregated αSYN, which recapitulates motor and non-motor dysfunctions seen in PD patients. We found that αSYN-induced motor dysfunction in mice is accompanied by an increased number of brain-residing Th17 (IL17+ CD4+) cells, but not CD8+ T cells. To evaluate whether the modulation of T cell response could rescue αSYN-induced damage, we chronically treated animals with abatacept (8 mg/kg, sc, 3x per week), a selective T-cell co-stimulation modulator. We found that abatacept treatment decreased Th1 (IFNƔ+ CD4+) and Th17 (IL17+ CD4+) cells in the brain, rescued motor function and prevented dopaminergic neuronal loss in αSYN-infused mice. These results highlight the significance of effector CD4+ T cells, especially Th17, in the progression of PD and introduce novel possibilities for repurposing immunomodulatory drugs used for arthritis as PD-modifying therapies.

Editorial sobre “Nuevas perspectivas en el manejo del cáncer de tiroides de bajo riesgo. Experiencia con la lobectomía tiroidea en una cohorte de 114 pacientes”

As the authors of the paper state, the management of low-risk differentiated thyroid cancer (DTC) remains controversial because of the indolent nature of the disease and the challenge of balancing morbidity of treatments with the risk of disease progression. The extent of thyroid resection is still a matter of debate: total thyroidectomy (TT) versus hemithyroidectomy (HT) (lobectomy plus isthmusectomy) using either a conventional neck incision or, in selected patients, a remoteaccess procedure, in this case the Transoral Endoscopic Thyroidectomy Vestibular Approach (TOETVA)1 . In the article published in this issue, Sacco et al. report the results of an observational study analyzing retrospective data obtained from the electronic medical records of a cohort of 114 patients with low-risk DTC managed with HT though different surgical approaches (neck incision and remote transoral approach) between January 2015 and April 2023. The number of TH proced

#2683 Targeted antibiotic modulation of the gut microbiome ameliorates hypertensive kidney damage

Abstract Background and Aims High blood pressure is associated with measurable inflammation, which precedes and promotes damage to the heart and kidneys. Microbiome-derived metabolites, particularly indole metabolites, modulate inflammation and host physiology, partially through aryl hydrocarbon receptor (AhR) signaling. To better understand the potential of a microbiome-targeting therapeutic approach to achieve organ protection in hypertension, we used narrow-spectrum antibiotics without enteral absorption to specifically deplete gram-negative or -positive bacteria in double transgenic rats (dTGR). Method Four-week-old dTGR (transgenic for human renin and angiotensinogen) were treated with oral Vancomycin (Vanco), Polymyxin B (Poly) or Vehicle (Veh) for 3 weeks. Seven-week-old SD rats were included as healthy controls. Microbiome, clinical and immune phenotype were analyzed by shotgun metagenomic sequencing, echocardiography, telemetric blood pressure (BP) measurement, clinical chemistry, bulk RNAseq and flow cytometry. Results Hypertensive kidney damage was ameliorated in Vanco treated dTGR, as assessed by renal Lcn2 expression, blood urea nitrogen and albuminuria. Vanco treated dTGR had significantly decreased cardiac hypertrophy. Poly treatment showed no effect. BP levels for both antibiotic treatments were not significantly different from Veh, despite a significantly improved endothelium-dependent and -independent vasorelaxation in isolated mesenteric arteries in both treated groups. Surprisingly, Vanco treatment led to a massive increase of gram-positive Lactobacilli and associated gene abundance for the production of indole lactic acid (ILA, via araT). We could previously show that ILA inhibits differentiation of pathological Th17 cells through AhR modulation. In line, Vanco treatment reduced the increased number of pathological Th17 in the kidney and intestine of dTGR. Poly treatment did not alter the inflammatory signature. Conclusion Modulation of the intestinal microbiome by narrow-spectrum antibiotics affects hypertensive organ damage. Our data underscores the importance of the gut microbiome in modulating hypertensive organ damage and helps to identify potential therapeutic strategies in the microbiome. Ongoing experiments investigate pro- and postbiotic therapeutic approaches and their AhR dependency.

The Effect of Granulocyte Colony-Stimulating Factor on Endometrial Receptivity of Implantation Failure Mouse.

The purpose of this study was to investigate the effect of G-CSF on the endometrial receptivity of implantation failure mice.Sixty female mice were treated mifepristone to establish an implant failure model. The treatment groups received different doses of G-CSF. Endometrial tissue and serum were collected on day 5 after mating. The abundance of pinopodes on the endometrium was observed by scanning electron microscopy. The expressions of LPAR3, COX2, and HOXA10 were detected by RT-qPCR and Western blotting. Serum levels of E2, P, VEGF, LIF, TNF-α and IL-10 were measured by ELISA. The expressions of VEGF, CD34, CD57, TNF-α, and IL-10 were assessed by immunohistochemistry. Immunofluorescence analysis was performed to determine the number of CD57, Treg, and Th17 cells.G-CSF increased implantation and pregnancy rates of mifepristone-induced implantation failure mice, with the most significant effect seen at the intermediate dose. G-CSF increased the serum levels of E2 and P, the abundance of endometrial pinopodes, and the level of LIF in the endometrium. It also promoted the expression of VEGF, HOXA10, LPAR3, and COX2. Moreover, G-CSF reduced the level of CD57 cells and the ratio of Th17/Treg cells in endometrium. G-CSF reduced the inflammatory factor TNF-α, but IL-10 did not change significantly.G-CSF can enhance embryo implantation rate and pregnancy rate and improve endometrial receptivity by attenuating degeneration of pinopodes, upregulating estrogen and progesterone, facilitating angiogenesis, maintaining immune cell homeostasis, and reducing the production of inflammatory cytokines in implantation failure mouse.

Immune cell balance as potential biomarker of progressing non-alcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a widespread chronic, slowly progressive metabolic multifactorial disease. It is represented by several clinical and morphological forms: steatosis, nonalcoholic steatohepatitis (NASH) (with or without fibrosis), and liver cirrhosis. The search for minimally invasive and cost-effective biomarkers of NAFLD is a key task in the diagnosis, staging of progression, and long-term monitoring of NAFLD. This article discusses the possibility of using immune cell balance as potential minimally invasive peripheral markers of NAFLD progression. In the progression of NASH from steatosis to fibrosis and cirrhosis, inflammation plays an important role because of the activation of Kupffer cells and increased migration of monocytes, dendritic cells, neutrophils, and activated T lymphocytes into the tissues. Macrophages originating from monocytes, with NASH progression, gradually begin to prevail over the pool of resident macrophages. The risk of NASH and fibrosis development in patients with NAFLD increases with the ratio of neutrophils/lymphocytes in the liver. An increase in the Th17 cell count and a decrease in T-regulatory cell count can contribute to increased hepatic steatosis and inflammation development in NAFLD and accelerate the transition from simple steatosis to steatohepatitis and fibrosis. Information on the participation of noncoding RNAs in the regulation of the balance of immune cells in NAFLD is presented, which also allows us to consider them as additional, along with cellular, markers of disease progression.

Blocking the CTLA-4 and PD-1 pathways during pulmonary paracoccidioidomycosis improves immunity, reduces disease severity, and increases the survival of infected mice.

Immune checkpoint pathways, i.e., coinhibitory pathways expressed as feedback following immune activation, are crucial for controlling an excessive immune response. Cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1) are the central classical checkpoint inhibitory (CPI) molecules used for the control of neoplasms and some infectious diseases, including some fungal infections. As the immunosuppression of severe paracoccidioidomycosis (PCM), a chronic granulomatous fungal disease, was shown to be associated with the expression of coinhibitory molecules, we hypothesized that the inhibition of CTLA-4 and PD-1 could have a beneficial effect on pulmonary PCM. To this end, C57BL/6 mice were infected with Paracoccidioides brasiliensis yeasts and treated with monoclonal antibodies (mAbs) α-CTLA-4, α-PD-1, control IgG, or PBS. We verified that blockade of CTLA-4 and PD-1 reduced the fungal load in the lungs and fungal dissemination to the liver and spleen and decreased the size of pulmonary lesions, resulting in increased survival of mice. Compared with PBS-treated infected mice, significantly increased levels of many pro- and anti-inflammatory cytokines were observed in the lungs of α-CTLA-4-treated mice, but a drastic reduction in the liver was observed following PD-1 blockade. In the lungs of α-CPI and IgG-treated mice, there were no changes in the frequency of inflammatory leukocytes, but a significant reduction in the total number of these cells was observed. Compared with PBS-treated controls, α-CPI- and IgG-treated mice exhibited reduced pulmonary infiltration of several myeloid cell subpopulations and decreased expression of costimulatory molecules. In addition, a decreased number of CD4+ and CD8+ T cells but sustained numbers of Th1, Th2, and Th17 T cells were detected. An expressive reduction in several Treg subpopulations and their maturation and suppressive molecules, in addition to reduced numbers of Treg, TCD4+, and TCD8+ cells expressing costimulatory and coinhibitory molecules of immunity, were also detected. The novel cellular and humoral profiles established in the lungs of α-CTLA-4 and α-PD-1-treated mice but not in control IgG-treated mice were more efficient at controlling fungal growth and dissemination without causing increased tissue pathology due to excessive inflammation. This is the first study demonstrating the efficacy of CPI blockade in the treatment of pulmonary PCM, and further studies combining the use of immunotherapy with antifungal drugs are encouraged.

Evaluation of pheromone traps for bark beetles and their predators in pine forests in the Kharkiv region

Introduction
 Pine stands of many regions have been affected by outbreaks of bark beetles with the dominance of Ips acuminatus (Gyllenhal, 1827) and Ips sexdentatus (B?rner, 1776). In many countries, pheromone traps are produced and used to monitor and suppress native and alien bark beetles. In Ukraine, pheromone traps for catching bark beetles are not produced. The effectiveness of various trap designs and the number of lures for pine bark beetles have not been previously studied in Ukraine. In 2023, within the framework of the FAO project TCP/RER/3801, State Specialized Forest Protection Enterprise ‘Kharkivlisozahyst’ received three types of pheromone traps produced by the Spanish company Sanidad agricola econex s.l. and pheromones intended for the capture of I. acuminatus and I. sexdentatus.
 The study aimed to compare the species composition and abundance of bark beetles and their predators by captures in the different pheromone trap-lure combinations.
 Materials and Methods
 The research was carried out in June – August 2023 in pure mature pine stands in the Vasishcheve subunit (State Specialized Forest Enterprise “Forests of Ukraine”, Branch “Zhovtneve Forestry”). Three types of pheromone traps were placed randomly in six locations of a homogeneous stand, the distance between which was about 50 meters. Type A traps (Funnel) contain 8 funnels, Type B traps are Theyson, and Type C traps are Crosstrap® mini. Depending on the experimental design, the traps contained blades with pheromones of Ips acuminatus or Ips sexdentatus. Blades for I. acuminatus contained 2 and 3 dispensers (commercial names 4C and 5C, respectively), and blades for I. sexdentatus contained 3 and 4 dispensers (commercial names 4C and 5C, respectively). In control treatments, respective traps (A, B, and C) were left empty (without blades). Trapping experiments were carried out from 20 June through 8 August 2023. Trapped insects were collected every 7 days, dried, and sorted. Bark beetles, longhorn beetles, and predators were identified at the species level, and some other insect groups at the family level at least.
 Results and Conclusions
 Five bark beetle species (Curculionidae: Scolytinae), five longhorn beetles (Cerambycidae), five predator species from Histeridae, Cleridae, Nitidulidae, Monotomidae, and Tenebrionidae, as well as several species of Staphylinidae, Carabidae, and Elateridae were captured in traps of three types (A – Funnel; B – Theyson; C – Crosstrap® mini) with pheromones of Ips acuminatus and I. sexdentatus. Target species – Ips acuminatus and I. sexdentatus – accounted for 51% and 31% of all captured beetles, respectively. Their numbers, seasonal dynamics, and proportions depended on the trap type, pheromone, and blade. The highest number of I. acuminatus beetles was captured in Crosstrap® mini traps (C type), and that of I. sexdentatus was found in Theyson traps (type B). An increase in dispenser number provides more captures of I. acuminatus and has no significant influence on captures of I. sexdentatus. The number of Th. formicarius was the lowest in trap B (Theyson) and the highest in trap С (Crosstrap® mini). The number of Th. formicarius captured in traps A and C with the pheromone of I. acuminatus was higher than in the traps with the pheromone of I. sexdentatus. Differences in the captured Th. formicarius beetles in the traps with more dispensers with the pheromone of I. acuminatus are significant, whereas in the traps with the pheromone of I. sexdentatus they are nonsignificant.
 12 Figs., 14 Refs.

New fraternine analogues: Evaluation of the antiparkinsonian effect in the model of Parkinson's disease

Venom-derived peptides are important sources for the development of new therapeutic molecules, especially due to their broad pharmacological activity. Previously, our research group identified a novel natural peptide, named fraternine, with promising effects for the treatment of Parkinson's disease. In the present paper, we synthesized three peptides bioinspired in fraternine: fra-10, fra-14, and fra-24. They were tested in the 6-OHDA-induced model of parkinsonism, quantifying motor coordination, levels of TH+ neurons in the substantia nigra pars compacta (SN), and inflammation mediators TNF-α, IL-6, and IL-1ß in the cortex. Peptides fra-14 and fra-10 improved the motor coordination in relation to 6-OHDA lesioned animals. However, most of the peptides were toxic in the doses applied. All three peptides reduced the intensity of the lesion induced rotations in the apomorphine test. Fra-24 higher dose increased the number of TH+ neurons in SN and reduced the concentration of TNF-α in the cortex of 6-OHDA lesioned mice. Overall, only the peptide fra-24 presented a neuroprotection effect on dopaminergic neurons of SN and a reduction of cytokine TNF-α levels, making it worthy of consideration for the treatment of PD.

Sodium butyrate alleviates R97-116 peptide-induced myasthenia gravis in mice by improving the gut microbiota and modulating immune response

Fermented butyrate exhibits an anti-inflammatory response to maintain immune homeostasis within the gut. However, the effect and underlying mechanism of butyrate on myasthenia gravis (MG) remain unclear. The changes in the gut microbiota and fecal contents of SCFAs in MG patients were examined. R97-116 peptide was used to induce the experimental autoimmune myasthenia gravis (EAMG) mice and sodium butyrate (NaB) was gavaged to the EAMG mice. Gut microbiota, the frequency of Th1, Th17, Treg, Tfh, and B cells, the levels of IFN-γ, IL-17 A, IL-10, IL-21, and anti-R97-116 IgG, RNA-seq of total B cells in the spleen were explored by metagenomics, flow cytometry, ELISA, and transcriptomics. A significant reduction in SCFA-producing bacteria including Butyricimonas synergistica and functional modules including butyrate synthesis/production II was observed in MG patients and fecal SCFAs detection confirmed the increase. The EAMG mice were successfully constructed and NaB supplementation has changed the composition and function of the gut microbiota. The numbers of Th1, Th17, Tfh, and B cells were significantly increased while that of Treg cells was obviously decreased in EAMG mice compared with controls. Interestingly, NaB treatment has reduced the amounts of Th17, Tfh, and B cells but increased that of Treg cells. Accordingly, the levels of IL-17 A, IL-21, and IgG were increased while IL-10 was decreased in EAMG mice. However, NaB treatment reduced IL-17 A and IL-21 but increased that of IL-10. RNA-seq of B cells has revealed 4577 deferentially expressed genes (DEGs), in which 1218 DEGs were up-regulated while 3359 DEGs were down-regulated in NaB-treated EAMG mice. GO enrichment and KEGG pathway analysis unveiled that the function of these DEGs was mainly focused on immunoglobulin production, mitochondrial respiratory chain complex, ribosome, oxidative phosphorylation, and CNS diseases including amyotrophic lateral sclerosis. We have found that butyrate was significantly reduced in MG patients and NaB gavage could evidently improve MG symptoms in EAMG mice by changing the gut microbiota, regulating the immune response, and altering the gene expression and function of B cells, suggesting NaB might be a potential immunomodulatory supplement for MG drugs.

Percentage of Th1 and Th17 cells and serum level of IL-17 and IFN-γ cytokines in COVID-19-associated mucormycosis.

The considerable number of the 2019 coronavirus disease (COVID-19) patients who developed mucormycosis infections in West and Central Asia urged a need to investigate the underlying causes of this fatal complication. It was hypothesized that an immunocompromised state secondary to the excessive administration of anti-inflammatory drugs was responsible for the outburst of mucormycosis in COVID-19 patients. Therefore, we aimed to study the implication of two major subsets of adaptive immunity T helper (Th)-1 and Th17 cells in disease development. Thirty patients with COVID-19-associated mucormycosis, 38 with COVID-19 without any sign or symptom of mucormycosis, and 26 healthy individuals were included. The percentage of Th1 and Th17 cells in peripheral blood, as well as the serum levels of interleukin (IL)-17 and interferon-gamma (IFN-γ), were evaluated using flow cytometry and ELISA techniques, respectively. Th17 cell percentage in patients with COVID-19-associated mucormycosis was significantly lower than in COVID-19 patients (P-value: <0.001) and healthy subjects (P-value: 0.01). In addition, the serum level of IL-17 in COVID-19 patients was significantly higher than that of healthy individuals (P-value: 0.01). However, neither the frequency of Th1 cells nor the serum level of IFN-γ was different between the study groups. Given the critical role of Th17 cells in the defense against mucosal fungal infections, these findings suggest that low numbers of Th17 and insufficient levels of IL-17 might be a predisposing factor for the development of mucormycosis during or after COVID-19 infection.

Syringaldehyde ameliorates mouse arthritis by inhibiting dendritic cell maturation and proinflammatory cytokine secretion.

Syringaldehyde (SD), a kind of flavonoid polyphenolic small molecule compound, has the antioxidant and anti-inflammatory properties. But it is unknown whether SD has properties on the treatment of rheumatoid arthritis (RA) by modulating dendritic cells (DCs). We explored the effect of SD on the maturation of DCs in vitro and in vivo. The results showed that SD significantly down-regulated the expression of CD86, CD40 and MHC II, decreased the secretion of TNF-α, IL-6, IL-12p40 and IL-23, and increased IL-10 secretion and antigen phagocytosis in vitro induced by lipopolysaccharides in a dose-dependent manner through reducing the activation of MAPK/NF-κB signaling pathways. SD also significantly inhibited the expression of CD86, CD40 and MHC II on DCs in vivo. Moreover, SD suppressed the expression of CCR7 and the in vivo migration of DCs. In arthritis mouse models induced by λ-carrageenan and complete Freund's adjuvant, SD significantly alleviated paw and joint oedema, reduced the levels of pro-inflammatory cytokines TNF-α and IL-6 and increased the level of IL-10 in serum. Interestingly, SD significantly decreased the numbers of type I helper T cells (Th1), Th2, Th17 and Th17/Th1-like (CD4+IFN-γ+IL-17A+), but increased the numbers of regulatory T cells (Tregs) in spleens of mice. Importantly, the numbers of CD11c+IL-23+ and CD11c+IL-6+ cells were negatively correlated with the numbers of Th17 and Th17/Th1-like. These results suggested that SD ameliorated mouse arthritis through inhibiting the differentiation of Th1, Th17 and Th17/Th1-like and promoting the generation of Tregs via regulation of DC maturation.

Ab-Initio molecular dynamics simulations of binary NaCl-ThCl4 and ternary NaCl-ThCl4-UCl3 molten salts

Molten salt reactor (MSR) with Thorium (Th) fuel cycle has attracted growing attention due to its merits such as safety, low radioactive waste production, and non-proliferation. The design and safe operation of MSR rely on a thorough understanding of the thermophysical properties of molten salts over a wide range of composition and temperature. However, experimental data of Th-based molten salts are limited due to the inherent challenges of dealing with corrosive molten salts and the radioactive nature of actinides. In this work, thermophysical properties including density, heat capacity, thermal expansion coefficient, and mixing energy of binary NaCl-ThCl4 and ternary NaCl-ThCl4-UCl3 molten salts are explored using ab-initio molecular dynamic simulations (AIMD) with the dDsC dispersion correction. The calculated mixing energy of binary NaCl-ThCl4 exhibits a minimum close to the eutectic composition. The heat capacity of the mixtures is linearly dependent on the mole fraction of each component. 7-fold and 6-fold coordinated Th complexes are dominant in the mixtures. 8-fold coordinated Th complex increases with ThCl4 fraction due to the formation of network structures. The average coordination number of Th exhibits a minimum near the eutectic composition. The minimum mixing energy for the ternary mixtures is observed in systems with a composition close to [NaCl]0.5[ThCl4]0.25[UCl3]0.25. The density positively deviates from the ideal solution in mixtures near this composition. These results are important to fill the data and knowledge gap of ThCl4 molten salts.

Distinct Patterns in Treg and T-helper Subset Reconstitution After Autologous Hematopoietic Stem Cell Transplantation in Juvenile-onset Systemic Sclerosis Patients

Systemic sclerosis (SSc) is a refractory autoimmune disease. In recent years, autologous hematopoietic stem cell transplantation (ASCT) has been performed to treat SSc. However, the reconstitution of immune components post-ASCT in SSc have not been fully described.We tested a total of 13 samples from 4 consenting SSc patients (median age: 18.5-years-old, 3F/1M) receiving IRB-approved immunoablation (TBI 600cGy) with lung/kidney shielding and Cytoxan (n = 3) or Thiotepa (n = 1) +/– Alemtuzumab followed by ASCT (CD34+ selected). Peripheral blood samples were collected at baseline, and 3, 6, 12, 24-months post-ASCT. By flow cytometry, we focused on the FOXP3+Treg and T-helper subset reconstitution.All 4 subjects experienced significant improvement in several clinical and quality of life parameters, especially in their skin disease evident within weeks after ASCT. T-cell recovery was evident by 6-months reaching pre-ASCT levels by 2-years post-ASCT (Fig. 1A). There was an increased percentage of FOXP3+Tregs in total CD4+T cells from 3- to 6-months post-ASCT (Fig. 1B), leading to an increase in the ratio of Treg/Tcon (Fig. 1B). The higher proportions of proliferating Tregs (Fig. 1C) likely led to their increased numbers. This trend was sustained until the last evaluation at 2-years post-ASCT (Fig. 1C). In contrast, CD4+Tcons showed a relatively lower proliferation rate, leading to a higher ratio of Ki67+Treg/Ki67+Tcon compared to pre-ASCT values (Fig. 1C). Notably, there was an increased proportion of Tregs expressing the skin-homing marker cutaneous lymphocyte-associated antigen (CLA) at 3-months lasting until the last test at 2-years post-ASCT (Fig. 1D), whereas CLA+/CD4+Tcons were less plentiful.The reconstitutions of T-helper (Th) subsets were also examined according to their chemokine receptor expression. Gradually decreased numbers of Th2, Th9, and Th17 were observed in the peripheral pool (Fig. 1E,1F). Nevertheless, the absolute number of Th1 and Th22 cells returned to levels seen pre-ASCT without any recurrence or flare of SSc symptoms.In summary, an increased number of circulating FOXP3+Tregs was observed leading to an elevated Treg/Tcon ratio in the peripheral pool. Skin-homing CLA+Treg subset was further enriched correlating with improved skin scores in all patients. The decrease of the Th2/Th9/Th17 subsets in the peripheral pool post-ASCT possibly contributes to the clinically less severe autoimmune phenotype. [Display omitted]

Intestinal colonization with Candida auris and mucosal immune response in mice treated with cefoperazone oral antibiotic.

Candida auris, an emerging multi-drug resistant fungal pathogen, causes invasive infections in humans. The factors regulating the colonization of C. auris in host niches are not well understood. In this study, we examined the effect of antibiotic-induced gut dysbiosis on C. auris intestinal colonization, dissemination, microbiome composition and the mucosal immune response. Our results indicate that mice treated with cefoperazone alone had a significant increase in C. auris intestinal colonization compared to untreated control groups. A significant increase in the dissemination of C. auris from the intestine to internal organs was observed in antibiotic-treated immunosuppressed mice. Intestinal colonization of C. auris alters the microbiome composition of antibiotic-treated mice. Relative abundance of firmicutes members mainly Clostridiales and Paenibacillus were considerably increased in the cefoperazone-treated mice infected with C. auris compared to cefoperazone-treated uninfected mice. Next, we examined the mucosal immune response of C. auris infected mice and compared the results with Candida albicans infection. The number of CD11b+ CX3CR1+ macrophages was significantly decreased in the intestine of C. auris infected mice when compared to C. albicans infection. On the other hand, both C. auris and C. albicans infected mice had a comparable increase of the number of Th17 and Th22 cells in the intestine. A significant increase in Candida-specific IgA was observed in the serum of C. auris but not in the C. albicans infected mice. Taken together, treatment with broad-spectrum antibiotic increased the colonization and dissemination of C. auris from the intestine. Furthermore, findings from this study for the first time revealed the microbiome composition, innate and adaptive cellular immune response to intestinal infection with C. auris.

Compound small peptide of Chinese medicine alleviates cyclophosphamide induced immunosuppression in mice by Th17/Treg and jejunum intestinal flora.

The aim of this study was to explore the efficacy of Compound small peptide of Chinese medicine (CSPCM) on cyclophosphamide (CTX) induced immunosuppression in mice. The 100 male Kunming mice were divided into 5 groups: group A (control group), group B (model group), group C (100 mg/kg.bw CSPCM), group D (200 mg/kg.bw CSPCM) and group E (400 mg/kg.bw CSPCM). At 1-3 days, mice of group B, C, D and E were intraperitoneally injected with 80 mg/kg.bw CTX. The results showed that compared with group A, the immune organ index, body weight change, RORγ T gene expression, RORγ T protein expression, CD3+ cell number, Th17 number and Alpha index, white blood cell count, lymphocyte count and monocyte count were significantly decreased in group B (p < 0.05), while Foxp3 gene expression, Foxp3 protein expression and Treg cell number were significantly increased (p < 0.05), CSPCM has a good therapeutic effect on the above abnormalities caused by CTX. CTX caused the decrease of intestinal flora richness and the abnormal structure of intestinal flora, and CSPCM could change the intestinal flora destroyed by CTX to the direction of intestinal flora of healthy mice. On the whole, CSPCM has a good therapeutic effect on CTX-induced immunosuppression in mice, which is reflected in the index of immune organs, the number of T lymphocytes and Th17 cells increased, the number of Treg cells decreased and the structure of intestinal flora was reconstructed.

Helicobacter pylori Chronic-Stage Inflammation Undergoes Fluctuations That Are Altered in tlpA Mutants.

Helicobacter pylori colonizes half of the world's population and is responsible for a significant disease burden by causing gastritis, peptic ulcers, and gastric cancer. The development of host inflammation drives these diseases, but there are still open questions in the field about how H. pylori controls this process. We characterized H. pylori inflammation using an 8-month mouse infection time course and comparison of the wild type (WT) and a previously identified mutant lacking the TlpA chemoreceptor that causes elevated inflammation. Our work shows that H. pylori chronic-stage corpus inflammation undergoes surprising fluctuations, with changes in Th17 and eosinophil numbers. The H. pylori tlpA mutant changed the inflammation temporal characteristics, resulting in different inflammation from the wild type at some time points. tlpA mutants have equivalent total and gland colonization in late-stage infections. During early infection, in contrast, they show elevated gland and total colonization compared to those by WT. Our results suggest the chronic inflammation setting is dynamic and may be influenced by colonization properties of early infection.

Регуляторные Т-клетки и T-хелперы 17-го типа с экспрессией эктонуклеотидаз CD39 и CD73 при тяжелой механической травме у детей

Frequent resulting disability and case mortality support the urgency of investigation of the immune response mechanisms triggered by severe injury (SI) in children. This study aimed to determine the informative immunological criteria of traumatic injury severity and prognosis in children (n = 43) based on the assessment of expression of CD39 and CD73 ectonucleotidase in populations of regulatory T cells (Treg, CD4+CD127lowCD25high) and T-helper 17 cells (Th17, CD4+CD161+CD3+) in SI cases grouped by the outcome (favorable (SIfav, n = 24), unfavorable (SIunfav, n = 17) and lethal (n = 2)). With the help of flow cytometry, we identified a pronounced decrease in the absolute number of Treg and Th17, as well as Treg and Th17 expressing CD39 and CD73, in the early post-traumatic period. In the SIfav and SIunfav groups the relative number of Treg and Th17 cells expressing CD39 differed significantly (p &lt;0.05); it was substantially higher form the first to the third day post injury in the SIunfav group. The level of Treg CD39 (44.4%) is a premise for an unfavorable outcome in children surviving an SI. In fatality cases, we registered extremely low ectonucleotidase expression rates: CD39+Treg — 9.52% (9.52–13.75) and CD39+Th17 — 0.92% (0.74–1.1). In the SIunfav group, the intensity of fluorescence (FL) of CD39 on Treg cells in the early post-traumatic period was higher than seen in the SIfav group. The threshold value for the average fluorescence intensity (FL) of CD39 on Treg was 8.25 c.u. In fatality cases, the Treg CD39 FL values were extremely low: 3.95 c.u. (3.7–4.67). The results of the study indicate that in children, the expression of CD39 and CD73 in Treg and Th17 populations is significantly associated with the severity of injury and outcome of the traumatic disease.