#Th17/Treg

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Effect of Qishan Formula Granules on Interventing Obesity Intestinal Microflora and Immune-Inflammatory by Wei Yan in Open Access Journal of Biogeneric Science and Research

ABSTRACT

Objective: To investigate the effects of Qishan Formula Granule on Simple Obesity and Intestinal Microflora-Inflammatory Immune Pathway. Methods: Eighty patients with simple obesity in our hospital were randomly divided into two groups: traditional Chinese medicine group and placebo group. The Chinese medicine group was treated with lifestyle intervention + Qishan formula granule, while the placebo group was treated with lifestyle intervention + placebo. The therapeutic effect, biochemical indexes, clinical symptoms, the number and composition of bacteria, the proportion of Th17/Treg cells in serum and inflammatory factors were measured before and after treatment. Results: After treatment, the total effective rate of simple obesity patients in Chinese medicine group was significantly higher than that in placebo group. (P ＜05). Compared with the placebo group after treatment, the biochemical indexes and clinical symptoms of the Chinese medicine group improved significantly after treatment. Further tests showed that Qishan Formula Granule could significantly improve the intestinal bacterial abundance, species and quantity of simple obesity patients. The levels of IL-17, TNF-alpha, Th17/Treg and LPS in patients with simple obesity in traditional Chinese medicine group were significantly lower than those in placebo group before and after treatment (P ＜ 0.05). Conclusion: Qishan Formula Granule can alleviate clinical symptoms of simple obesity and improve treatment efficiency through intestinal flora-inflammatory immune pathway.

KEYWORDS: Qishan formula granule; Obesity; Intestinal flora; Immune inflammatory; Th17/Treg

In recent years, with the change of people's lifestyle, the incidence of obesity has increased rapidly. For the chronic metabolic disorders celected to obesity and overweight, the prevalence of diseases such as diabetes and cardiovascular and cerebrovascular diseases has increased year by year [1]. Obesity cannot only lead to diabetes or high incidence of cardiovascular and cerebrovascular events, but also closely relate to cancer, depression, asthma, apnea syndrome, infertility, osteoarthropathy, fatty liver and many other diseases [2-5]. Therefore, it has become a serious impact on people's health, it’s urgent to find reasonable and effective intervention measures. At present, the main drugs of weight loss treatment include non-central drugs, central drugs and hypoglycemic drugs, which have many problems such as low effective response rate, large side effects and weight rebound after stopping [6]. The combination of diet and exercise is often difficult to adhere to for a long time, and compliance is poor [7]. Seeking effective drugs or methods to treat simple obesity has become an important research hotspot in recent years.

It is believed that intestinal flora plays an important role in the regulation of immune inflammation and glycolipid metabolism [8,9]. Studies have shown that there is chronic low-level inflammation in obese people, and chronic low-level inflammation caused by obesity may promote the occurrence development of metabolic disorders [10]. At the same time, it has been found that the disorder of intestinal flora and its metabolites in obesity patients and the obvious imbalance of proportion can affect the formation and differentiation of immune cells such as Th17 cells and Treg cells, thus leading to chronic low-level immune inflammation and obesity [11-13]. At present, a number of studies have shown that traditional Chinese medicine has an important effect on intestinal flora, berberine, Gegenqinlian decoction, tonifying traditional Chinese medicine and so on have a certain degree of adjustment of bacterial dysbiosis [14-15]. Qishan formula granules from Gegenqinlian modification, is a national famous old Chinese medicine experience prescription. The results of the previous study showed that Qishan formula has the effect of reducing blood sugar, improving insulin resistance and reducing body weight. However, the mechanism is not clear, and the simple obesity population has not been studied. Therefore, this study explores the efficacy of Qishan Formula Granule in the treatment of simple obesity and its effect on intestinal flora immune inflammatory pathway, in order to provide reference for traditional Chinese medicine in the treatment of obesity.

INFORMATION AND METHODOLOGY

General Information

In this study, A randomized (randomized digital approach), double-blind（The subjects, researchers, surveyors or data analysts did not know the treatment allocation, placebo-controlled, prospective study approach was selected for simple obese patients through health check-ups, community population screening, and outpatient visits. All patients were treated with lifestyle intervention（In a low sugar diet, 200-350g of main food should be eaten every day, and the ratio of carbohydrate to total calories should be 50% - 65%. Low fat diet, fat intake within 50g, about 30% of the total calories. Protein balance, about 15% of the total heat. Encourage the intake of foods rich in dietary fiber and vitamins. The daily total heat is controlled within 100kj / kg. Adhere to moderate intensity aerobic exercise, i.e., heart rate + 170 age after exercise, at least 3-5 days a week. It lasts for half a year; those with diabetes were treated with glizat sustained-release tablets; and those with hypertension were treated with amlodipine. The study included 80 patients who still met the following criteria after the 1-month elution period. a random number table was established using excel software. the standard 80 patients were randomly averaged into two groups: the traditional medicine group (40) and the placebo group (40). In the group of traditional Chinese medicine,14 cases were male and 26 cases were female; the age was 25-50 years, the average age was 38.74±10.23 years; and the average course of disease was 6.63±3.55 years. in the placebo group,16 men and 24 women; age 25-50 years, mean age 39.61±9.83 years; and mean course of disease 6.17±3.82 years.

Inclusion and Exclusion Criteria

Inclusion Criteria

(1)Patients with simple obesity (male waist ≥90 cm, female ≥85 cm, and BMI≥25 kg/m2) in accordance with the 2011 edition of the Expert Consensus on the Prevention and Control of Adult Obesity in China;(2) age greater than 25 years of age less than 70 years of age;(3) classification of TCM syndrome differentiation as obesity-wet-heat accumulation of spleen syndrome ：The body is fat（25kg/m2≤BMI≤28kg/m2：+1score, 28kg/m2≤BMI≤30kg/m2：+2scores, 30kg/m2≤BMI：+3scores,）; the abdomen is full(+1score); the food is little and tired(+1score); the head is heavy as wrap(+1score),The loose stool is not good(+1score); the urine color is yellow(+1score); and the whole body is hot and humid jaundice(+1score);The tongue is fat(+2scores); with yellow and greasy fur(+2scores);and smooth veins(+2scores);(4) discontinuation of drugs affecting weight for 4 weeks; (5) signing of informed consent.

Exclusion Criteria

(1)Weight gain due to drugs, endocrine diseases or other diseases;(2) severe liver and kidney dysfunction or other severe primary diseases;(3) history of acute cardiovascular and cerebrovascular events or myocardial infarction within 6 months;(4) stress state or secondary blood glucose elevation or secondary hypertension;(5) weight-loss surgery within one year;(6) severe dyslipidemia;(7) unwillingness of cooperators (who cannot cooperate with dietary control or do not use drugs as prescribed);(8) mental illness, tumor patients;(9) women with or breast-feeding, and women with planned or unplanned contraception;(10) possible allergy to gestational drugs;(11) patients with diabetes who have received medication.

Treatment

(1) The Chinese medicine group was given lifestyle intervention + qishan formula granules orally, one pack at a time, twice a day. (The formulas are: Pueraria root 15g, Scutellaria baicalensis 10g, Coptis chinensis 10g, Rhubarb 3g, gynostemma pentaphyllum 10g, Shengqi 20g, Huai yam 20g, Atractylodes chinensis 15g, Poria cocos 15g, fried Fructus Aurantii 10g, Raw Hawthorn 10g, Chuanxiong 10g, produced by the preparation room of traditional Chinese medicine in our hospital). (2) The placebo group was given a lifestyle intervention plus a placebo oral dose, twice daily. (The formulas are: starch, pigment and adhesive, which are produced by the traditional Chinese medicine preparation room of our hospital).

Indicator Measurements

Fasting blood glucose (FPG), blood lipids, blood pressure, waist-to-hip ratio, body mass index (BMI), body fat content, tcm symptom score (and other biochemical indicators, clinical symptoms were measured every 4 weeks. HbA1c, fasting insulin (FINS), fecal intestinal flora, proportion of serum th17/treg cells and serum IL-17, TNF-α, liver and kidney function, blood routine, urine routine, electrocardiogram were measured at week 0 and 12.

Determination of Flora Size and Composition

Quantitative intestinal excreta were diluted and inoculated into bs medium (bifidobacterium isolate) anaerobic culture for 48 h, bbe medium (bacillus isolates) anaerobic culture for 24h, lactic acid bacteria selective medium for 24h, enterococcal agar for 24h, fs medium (clostridium isolates) for 72h, kf streptococcus agar (streptococcus isolates) anaerobic culture for 24 h, and iridium agar for 24h. After the growth of the colony, the desired target bacteria were identified by colony morphology, Gram staining and biochemical reaction. On a variety of different media, the colonies were identified, and the number of each bacteria was compared with the reference value, and the B/E value was calculated to evaluate the number and composition of intestinal flora in patients with simple obesity after oral intervention of Qishan without sugar.

PCR-DGGE Analysis Intestinal Flora Composition

Fecal specimen collection and DNA extraction: The collection of feces of simple obese patients by aseptic method was about 1 g in 2 mL EP tube, and the stool genomic DNA was extracted according to the instructions of the DNA extraction kit.pcr: the v3 section of bacterial 16srdna was amplified by universal primers. the amplification conditions were 94°c for 3 min predenaturation,94° c for 1 min denaturation,55°c for 1 min annealing,72°c for 1 min extension, a total of 36 cycles,72°c for 10 min extension, and 4°c preservation.PCR products were detected by 2% agarose gel electrophoresis and stored at -20°C.dgge: the pcr product was separated on 8% polyacrylamide glue, the gel was stained by gelred after the end, the gs-800 grayscale scanner was imaged, and the correlation analysis of dgge molecular fingerprint was performed by biomerics software.

Quantitative Quantitative PCR Analysis of Intestinal Microflora

Fecal specimen collection and DNA extraction: The collection of feces of simple obese patients by aseptic method was about 1 g in 2 mL EP tube, and the stool genomic DNA was extracted according to the instructions of the DNA extraction kit. PCR primer design: according to Bifidobacterium, Lactobacillus, Escherichia coli, Bacillus, Clostridium, Streptococcus 16SrDNA gene sequence, the corresponding bacterial PCR primer was designed, and the specificity of the corresponding bacterial sequence was compared in the BLAST gene bank. Preparation of the standard curve: the PCR products of each bacteria in the control group were purified according to the instructions of the DNA purification kit, and the absorbance (A value) and concentration of the purified product were determined, and the copy number of each standard product 1μl was converted to be used to make the standard curve.

Detection of Biochemical Indexes

Blood sugar, blood lipids and other biochemical indicators were determined by the Olimpas 2000 large automatic biochemical instrument. serum insulin, hba1c was determined by our advia centur®xp fully automated chemiluminescence immunoanalyzer. Serum LPS was detected by ELISA. Methods for the determination of intestinal flora and SCFAs:2g of fresh feces of patients were frozen at -20°C refrigerator with a toilet provided by the Institute of Microbiology of Zhejiang Province (containing stabilizer), and the Institute was commissioned to test it. Body fat content was determined by the department's own body fat tester.HOMA-IR is calculated by formula HOMA-IR = FPG × FINS /22.5, HOMA-IS is calculated by formula HOMA-IS =1/HOMA-IR=22.5/ FPG × FINS.

Anges Of Th17/Treg Cells Before and After Intervention

The peripheral blood of the two groups of patients was collected, standing for 1 h,2000 rpm,4°c, centrifuged for 10 min, collected and packed into supernatant, and stored at -20°c when not detected in time. the content of serum il-17, tnf- α was determined by double antibody sandwich enzyme-linked immunosorbent assay (elisa), and the specific operation was carried out strictly according to the instructions of elisa kit. cd3-pecy7 and cd4-pe 0.5μg each, after oscillating and mixing evenly, incubated at room temperature for 30 min;300 g centrifuged for 5 min. after washing with cold pbs,1 ml of diluted fixed, membrane-penetrating agent was added. after reaction for 50 min, the concentration of th17 and treg cells was determined by flow cytometry.

Safety Evaluation and Adverse Reaction Management

If there is an alt increase during medication, the principle of adjusting the drug dose or interrupting treatment is:1 If the alt increase is within 2 times the normal value, continue to observe. If ALT rises at 2-3 times the normal level and is taken in half, continue to observe if ALT continues to rise or remains between 80-120 U.L-1 and interrupt treatment. 3 If ALT rises above 3 times the normal value, stop the drug. After the withdrawal of drugs return to normal can continue to use, and strengthen the treatment of liver protection and follow-up. If leukopenia occurs during medication, the principles for adjusting the drug dose or interrupting treatment are as follows:1 If leukopenia is not lower than 3.0 x 109·L-1, continue to take medication to observe. If the white blood cell drops between (2.0 and 3.0) ×109·L-1, observe in half. Most patients can return to normal during continued medication. If the review of leukocytes is still below 3.0 x 109·L-1, the treatment is interrupted. 3 If leukopenia falls below 2.0 x 109·L-1, interrupt treatment.

CRITERIA FOR EVALUATION OF SYNDROME EFFICACY

Clinical recovery: TCM clinical symptoms, signs disappear or basically disappear, syndrome score reduction ≥90% and weight lost by ≥ 15%. Remarkable effect: the clinical symptoms and signs of TCM were obviously improved, and the score of syndromes was reduced by more than 70% and weight lost by ≥ 10%. Effective: TCM clinical symptoms, signs are improved, syndrome score reduction≥30% and weight lost by ≥ 5%. Invalid: TCM clinical symptoms, signs are not significantly improved, or even aggravated, syndrome score reduction <30% or weight lost by<5%. Total effective = (clinical recovery + significant + effective)/ total number *100%.

Statistical Analysis

Statistical software SPSS 17.0 is used to compare and analyze the indexes in this paper. The measurement data are expressed in form, and the measurement data are normally distributed, which meet the t-test standard.T-test to compare the counting data with xs test comparison; the count data are compared by Χ2 test; when p < 0.05, the statistics have significant differences.

Estimation of Sample Size

Estimation of sample size: according to the estimation method of sample size in clinical experimental research, the sample size of two sample mean comparison is estimated. Check the "sample size table required for two sample mean comparison". According to the bilateral α = 0.05, the test efficiency (1- β) = 0.9, μ 0.05 = 1.96, μ 0.1 = 1.28, according to the previous research experience, σ is the estimated value of the overall standard deviation of two samples = 16, δ is both samples. The difference of number = 3.0, and the result is n = 34. Considering the loss rate of sample 15%, 40 cases in the experimental group and 40 cases in the control group were preliminarily determined.

RESULTS

The rate of abscission and baseline were compared between the two groups. In the placebo group, 40 cases were enrolled, 2 cases were dropped, 38 cases were observed, and the drop rate was 5%. In the treatment group of traditional Chinese medicine, 40 cases were enrolled, 3 cases fell off, 37 cases were observed, the rate of falling off was 7.5%. There were 12 diabetic patients in placebo group, 15 hypertensive patients, 13 diabetic patients and 14 hypertensive patients in traditional Chinese medicine treatment group. There was no significant difference between the two groups in the proportion of diabetic and hypertensive patients. The age gender, baseline FPG, total cholesterol, triglyceride, LDL, BMI, body fat content, HbA1c, fins, waist to hip ratio, TCM syndrome score and the number of specific intestinal flora were comparable.

Groups Comparison of Clinical Effect of Simple Obesity Patients After Treatment

Compared with the placebo group after treatment, the total effective rate of simple obese patients in the traditional chinese medicine group was significantly increased after treatment (81.1% vs 50.0 %), and there was a significant difference in comparison (p <0.05). the clinical efficacy of the two groups was compared in table 1. Further observation found that the two groups of patients did not have liver function, renal function, abnormal white blood cell level and other adverse reactions Table 1.

Two Groups Comparison of Biochemical Indexes of Simple Obesity Patients Before and After Treatment

Compared with the previous treatment, the indexes of the patients with simple obesity in placebo group did not change significantly after treatment, and there was no significant statistical difference (P >0.05). The scores of FPG, total cholesterol, triglyceride, low-density lipoprotein, BMI, body fat, HbA1c, FINS, waist-to-hip ratio and TCM syndromes were significantly lower in patients with simple obesity than before and after treatment group of placebos, whereas HDL was significantly higher than that before and after treatment placebo group, there was a significant difference in comparison (P <0.05); the comparison of biochemical indexes before and after treatment in the two groups was shown in Table 2.

Groups Patients with simple obesity before and after treatment Comparison of intestinal flora

The colony numbers of Bifidobacterium, Bacillus fragilis, Lactobacillus, Enterococcus and Escherichia coli in the placebo group were not significantly different after treatment compared with that before and after treatment (P >0.05). The colony numbers of Bifidobacterium and Bifidobacterium in the traditional Chinese medicine group were significantly higher than those in the comfort group before and after treatment (P <0.05). A similar result was found for the detection of bacterial copy number of each stool by real-time fluorescence quantitative PCR, and the real-time fluorescence quantitative PCR is shown in Table 4.

Two Groups Comparison of Inflammatory Indexes in Simple Obesity Patients Before and After Treatment

Compared with pre-treatment, the inflammatory indexes of patients with simple obesity in placebo group did not change significantly after treatment (P >0.05)The levels of IL-17, TNF-α and Th17/Treg were significantly lower in patients with simple obesity than those before and after treatment placebo group, there was a significant difference in comparison (P <0.05); the comparison of biochemical indexes before and after treatment in the two groups was shown in Table 5.according to the relationship between th17/treg level and normal range after treatment of qishan formula granules, it was divided into normal group (th17/treg level was within normal range) and high level group (th17/treg level was higher than normal range). Further statistics found that the total amount of intestinal flora after treatment in the normal group was significantly higher than that in the high-level group (P <0.05, Fig.1) Table 3.

DISCUSSION

In recent years, with the rapid development of today's society, people's life style and diet, nutrition structure has undergone great changes, so the incidence of obesity remains high, and the incidence of diabetes, cardio-cerebrovascular diseases and other diseases caused by obesity is increasing year by year. Several studies have shown that Qishan formula granules play an important role in reducing body weight. Therefore, this study discussed the effect of Qishan formula granule on simple obesity and further discussed its mechanism.

This study found that the total effective rate of simple obesity patients was significantly increased after the intervention of qishan formula granules. at the same time, the intervention of qishan formula granules could improve the clinical symptoms and biochemical indexes such as blood sugar and blood lipids in simple obesity patients. The application of Qishan formula granules is beneficial to the treatment of simple obese patients. The theory of traditional Chinese medicine believes that obesity is due to dietary fat, inactivity,dysfunction of spleen in transportation, accumulation of phlegm and dampness cream. Body diseases characterized by obesity and fatigue. Its most common symptom is damp-heat accumulation spleen syndrome [16,17]. Qishan formula granules from Gegenqinlian decoction and six gentleman decoctions reduced. Raw astragalus, huai yam, poria qi invigorating spleen, Scutellaria baicalensis, Coptis chinensis Qingzhongjiao dampness and heat, rhubarb, gynostemma pentaphyllum to remove dampness, Atractylodes aromatization and dampness, Fructus Aurantiii, Hawthorn Qi digestion, phlegm elimination, Pueraria, Chuanxiong heat Qingjin Qi Huoxue. Thus, it has the effect of invigorating qi and invigorating spleen, clearing away heat and removing dampness and removing turbidity. It can make temper health transport and water Tianjin four cloth, phlegm turbidity inside the heat clear and fat in the full elimination. The purpose of removing Glycyrrhiza in the original prescription of Gegen Qinlian decoction is to prevent the rise of blood sugar and the storage of water and sodium.Therefore, the application of Qishan formula granules can significantly improve the total effective rate of patients and significantly improve clinical symptoms, blood sugar, blood lipids and other biochemical indicators. However, the mechanism of cell biology and molecular biology has not been elucidated Table 5.

Several studies have pointed out that differences in the composition of the intestinal flora are one of the most important causes of obesity, and their mechanisms mainly involve activating inflammatory responses, promoting energy absorption and regulating intestinal permeability [18,19] Studies have shown that obese patients are often accompanied by inflammatory signaling pathway activation, immune cell infiltration and other pathological changes [20]. therefore, stopping from the intestinal flora-inflammatory immune pathway will be helpful to elucidate the mechanism of qishan formula granules to improve simple obesity. this study examined the number and composition of intestinal flora and found that the colony numbers lactic acid bacteria, bifidobacterium and bacteroides were significantly higher in patients with simple obesity than in the placebo group before and after treatment after treatment after treatment with qishan formula granules. The results showed that Qishan formula could significantly affect the intestinal flora of simple obese patients. He Xuyun and other studies have found that Astragalus polysaccharide, the main ingredient of Astragalus membranaceus, can significantly inhibit the formation of obesity in mice and significantly restore intestinal flora disorders [21]. At the same time, several studies have pointed out that Radix Puerariae, Scutellariae, Coptis, Huai yam, Ligusticum chuanxiong, Poria cocos and Astragalus membranaceus It can affect the composition and richness of intestinal flora [22-25]. thus further confirming the effect of Qishan formula granules on intestinal flora.Intestinal flora plays an important regulatory role in the balance of immune cells. Fang Qian et al found a linear positive correlation between Bifidobacterium/ Escherichia coli ratio and Treg/Th17 in children with asthmatic bronchitis [26]. At the same time, numerous studies have found that berberine regulates the intestinal flora and the balance of Th17/Treg cells in rats, while the disruption of the balance between pro-inflammatory Th17 cells and inhibitory Treg cells is a key factor in many immune and metabolic diseases [27-29]. Therefore, the effect of Qishan formula granules on inflammatory cells and inflammatory factors was further examined. the results showed that il-17, tnf-α, th17/treg and levels were significantly reduced in patients with simple obesity after intervention of qishan formula granules, indicating that qishan formula granules could affect the inflammatory response in patients with simple obesity. further exploring the relationship between th17/treg levels and intestinal flora found that the total amount of intestinal flora in patients with th17/treg levels in the normal range was significantly higher than that of patients with th17/treg levels than normal, indicating a association between intestinal flora and treg/th17 values in patients with simple obesity. In summary, Qishan formula granules can improve the symptoms of obesity by increasing the richness and diversity of intestinal flora in simple obese patients and inhibiting the inflammatory response.

To sum up, this study found that Qishan formula granules can alleviate the clinical symptoms of simple obesity and improve the treatment efficiency through the intestinal flora-inflammatory immune pathway. Qishan formula granules can regulate the proportion of Th17, Treg cells and the secretion level of inflammatory factors by influencing the composition and richness of intestinal flora, so as to reshape the body shape and improve the biochemical index, and then achieve the purpose of treating simple obesity. However, there are still some shortcomings in this study, and it is necessary to further explore the main components of its efficacy and how the intestinal flora affects the inflammatory response.

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The T Cell Landscape

T cells, a critical component of the adaptive immune system, stand as the body's elite force in combatting infections and diseases. These specialized lymphocytes boast remarkable diversity, each type playing a distinct role in orchestrating a targeted and effective immune response.

T cells, like all blood cells, originate from hematopoietic stem cells residing in the bone marrow. However, their training ground lies within the thymus, a specialized organ located in the chest. Here, they undergo a rigorous selection process known as thymocyte education. During this process, immature T cells, called thymocytes, are presented with self-antigens (molecules unique to the body) by special cells. Thymocytes that bind too strongly to these self-antigens are eliminated, preventing them from attacking healthy tissues later. Only thymocytes that demonstrate the ability to recognize foreign invaders while exhibiting tolerance to self are released into the bloodstream as mature T cells.

Following this rigorous training, mature T cells exit the thymus and embark on their patrol, circulating throughout the bloodstream and lymphatic system. They remain vigilant, constantly scanning for their specific targets – antigens. Antigens are foreign molecules, such as fragments of viruses, bacteria, or even cancerous cells, that trigger the immune response.

The hallmark of a T cell is its T cell receptor (TCR), a highly specialized protein complex embedded on its surface. This receptor acts like a lock, uniquely shaped to fit a specific antigen, the "key." Each T cell develops a unique TCR capable of recognizing only a single antigen, enabling a highly specific immune response.

But how do T cells encounter these hidden antigens lurking within infected or cancerous cells? This critical role is played by antigen-presenting cells (APCs). APCs, such as macrophages and dendritic cells, engulf pathogens or abnormal cells, break them down into smaller fragments (peptides), and present them on their surface complexed with major histocompatibility complex (MHC) molecules. MHC molecules act as identification tags, allowing T cells to distinguish between "self" and "non-self." When a T cell's TCR encounters its specific antigen bound to an MHC molecule on an APC, a dance of activation begins. The T cell becomes stimulated, and a cascade of signaling events is triggered. This leads to the T cell's proliferation, producing an army of clones specifically tailored to combat the recognized threat.

T cells are not a single, monolithic entity. They comprise a diverse population, each type with a specialized function:

Helper T Cells (Th Cells):

Helper T cells, often abbreviated as Th cells, play a central role in coordinating immune responses. They express the CD4 surface marker and can recognize antigens presented by major histocompatibility complex class II (MHC-II) molecules. Subtypes of helper T cells include Th1, Th2, Th17, and regulatory T cells (Tregs), each with distinct functions and cytokine profiles.

Th1 cells mediate cellular immunity by activating macrophages and cytotoxic T cells, crucial for defense against intracellular pathogens.

Th2 cells are involved in humoral immunity, promoting B cell activation and antibody production, thus aiding in defense against extracellular parasites.

Th17 cells contribute to the immune response against extracellular bacteria and fungi, producing pro-inflammatory cytokines. Regulatory T cells (Tregs) maintain immune tolerance and prevent autoimmunity by suppressing excessive immune responses.

Cytotoxic T Cells (Tc Cells):

Cytotoxic T cells, also known as Tc cells or CD8+ T cells, are effector cells responsible for directly killing infected or aberrant cells. They recognize antigens presented by MHC class I molecules on the surface of target cells. Upon activation, cytotoxic T cells release perforin and granzymes, inducing apoptosis in target cells and eliminating the threat.

Memory T Cells:

Memory T cells are a long-lived subset of T cells that persist after the clearance of an infection. They provide rapid and enhanced immune responses upon re-exposure to the same antigen, conferring immunological memory. Memory T cells can be either central memory T cells (TCM), residing in lymphoid organs, or effector memory T cells (TEM), circulating in peripheral tissues.

γδ T Cells:

Unlike conventional αβ T cells, γδ T cells express a distinct T cell receptor (TCR) composed of γ and δ chains. They recognize non-peptide antigens, such as lipids and metabolites, and are involved in immune surveillance at epithelial barriers and responses to stress signals.

Beyond the Battlefield: The Expanding Roles of T Cells: The remarkable capabilities of T cells have opened doors for several groundbreaking applications in medicine:

Vaccines: By presenting weakened or inactivated forms of pathogens, vaccines "train" the immune system to generate memory T cells. This prepares the body to recognize and rapidly eliminate the real pathogen upon future exposure, preventing disease.

Cancer immunotherapy: CAR T-cell therapy, a revolutionary approach, genetically engineers a patient's own T cells to express chimeric antigen receptors (CARs) that recognize and target specific cancer cells. These "supercharged" T cells are then reintroduced into the patient, unleashing a potent attack against the tumor.

Autoimmune disease treatment: Researchers are exploring ways to manipulate T cells to suppress harmful immune responses that underlie autoimmune diseases like rheumatoid arthritis and multiple sclerosis.

The diverse array of T cells underscores the immune system's complexity and adaptability in mounting tailored responses against a myriad of threats. From orchestrating immune reactions to maintaining tolerance and establishing long-term immunity, T cells play multifaceted roles in safeguarding the body's health. Understanding the intricacies of T cell biology not only sheds light on immune-mediated diseases but also paves the way for developing novel therapeutic strategies harnessing the power of the immune system.

T cells represent a fascinating aspect of immunology, with their diversity and specificity driving the complexity of immune responses. As research advances, further insights into T cell biology promise to revolutionize immunotherapy and enhance our ability to combat diseases ranging from infections to cancer. By understanding and harnessing their power, we can unlock new avenues for protecting and improving human health.

[popgenpapers]

Th17 cells with a pathogenic signature in joints of ZAP-70 mutant arthritic mice harbor unique TCR repertoires that share features with WT Tregs

http://dlvr.it/T3dKYH

[tumimmtxpapers]

FOXO1 regulates Th17 cell-mediated hepatocellular carcinoma recurrence after hepatic ischemia-reperfusion injury

CONCLUSIONS: These results indicated that FOXO1-Th17/Treg axis exerts a crucial role in IRI-mediated immunologic derangement and HCC recurrence, which could be a promising target for reducing the HCC recurrence after hepatectomy. Liver IRI affects the balance of Th17/Treg cells by inhibiting the expression of FOXO1, and the increase of Th17 cells has the ability to induce HCC recurrence through EMT program, cancer stemness pathway, the formation of premetastatic microenvironment and... http://dlvr.it/SqrPkM

[sommesick]

Together, these findings suggest that TAp63 is intricately linked to the balance of Th17 and Treg cell differentiation. Thus, inhibiting TAp63 could enhance the suppressive function of Treg cells and limit autoimmune RA.

These findings reveal a robust mechanism for MTX action and show how Treg cells can be preserved in RA. They also demonstrate the potential of TAp63 as a new therapeutic target for RA.

[juniperpublishers-crdoj]

Effect of Arginase-1 Inhibition on the Incidence of Autoimmune Diabetes in NOD Mice

Authored by Peter Buchwald

Abstract

Metabolism of the amino acid L-arginine is implicated in many physiological and pathophysiological processes including autoimmune conditions such as type 1 diabetes (T1D). Alternate arginine metabolism through the citrulline-nitric oxide (NO) or the ornithine pathways can lead to proinflammatory or immune regulatory effects, respectively. In this report, we blocked the arginine-ornithine metabolic pathway by inhibiting the enzyme arginase-1 with Nω-hydroxy-nor-arginine (nor-NOHA) to make arginine more available to the alternate citrulline pathway for augmented NO production and increased incidence of autoimmune T1D in female non-obese diabetic (NOD) mice. Unexpectedly, mice receiving nor-NOHA did not develop diabetes although increased NO production is proinflammatory and expected to increase diabetes incidence. These results warrant further studies of the mechanism of action of nor-NOHA, and highlight its potential as a therapeutic agent for the treatment or prevention of T1D.

Keywords: nor-NOHA; T1D; NOD; Incidence rate; Arginine; Metabolism; Ornithine; Nitric oxide; Inflammation; Macrophages

Abbrevations:nor-NOHA: Nω-hydroxy-nor-arginine; T1D: Type 1 Diabetes; NOD: Non-Obese-Diabetic; D-NOD: Diabetic NOD; ND-NOD: Non-Diabetic NOD; NO: Nitric Oxide; iNOS: Induced Nitric Oxide Synthase; Arg-1: Arginase-1; ODC: Ornithinedecarboxylase; DFMO: Di-fluoromethyl-ornithine

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Introduction

The role of L-arginine metabolism in autoimmune diseases has recently become of interest. Specifically, metabolic products of two alternate arginine metabolism pathways (Figure 1) are implicated in both proinflammatory/autoimmune and immune regulatory/tolerogenic immune responses. The argininecitrulline- nitric oxide (NO) pathway favors proinflammatory polarization of innate (M1-like) and adaptive (Th1/Th17) immune cells. For example, when enough arginine substrate is available and the enzyme NO synthase (NOS or iNOS) is upregulated, NO production increases in pro-inflammatory M1 macrophages. Depending on its level, NO can be either pro- and or anti-inflammatory. Whereas, high levels of NO are proinflammatory and cytotoxic, and promote both apoptosis and necrosis in target cells [1,2], low levels have been shown to have anti-inflammatory effects [3-5]. On the other hand, the alternate ornithine pathway of arginine metabolism favors polarization towards immunoregulatory function in immune cells such as regulatory T cells (Tregs) and M2 macrophages, which are essential during resolution of inflammation, tissue healing, and immune tolerance induction/maintenance. When the enzyme arginase-1 is overexpressed, arginine is metabolized to urea, ornithine, and downstream polyamines that are crucial building blocks during cell proliferation and maintenance of tissue homeostasis. Therefore, we hypothesized that administration of an arginase-1 inhibitor should block the urea-ornithine pathway making arginine more available for the alternate citrulline- NO pathway for increased production of NO and associated tissue inflammation and, ultimately, increased incidence of autoimmune diabetes (Figure 1).

Nor-omega-hydroxide-L-arginine (nor-NOHA) is a competitive inhibitor of arginase-1 that should increase arginine availability to the NO pathway, whereby, increasing the production of NO [6]. To our knowledge there are no available reports on the effect of nor-NOHA on the autoimmune process in animal models of type 1 diabetes (T1D). The non-obesediabetic (NOD) mouse is a widely used model of human T1D and provides an attractive opportunity to investigate the effect of nor-NOHA on the incidence of autoimmune diabetes [7,8]. The diagram shown in Figure 1 illustrates a working model of the effect arginine metabolism and nor-NOHA treatment on diabetes incidence in diabetes-prone female NOD mice. In the current study, we investigated arginine metabolism and the spontaneous incidence of autoimmune diabetes as a function of age in female NOD mice, and evaluated the effect of nor-NOHA treatment on diabetes incidence.

Simplified scheme/model of alternate arginine metabolism either through the urea-ornithine or the citrulline-nitric oxide (NO) pathways leading to anti-or pro-inflammatory effects, respectively, and associated decrease or increase in diabetes incidence. The scheme also illustrates the effect of nor-NOHA on arginase-1 (Arg-1) and the production of ornithine and downstream polyamines by ornithinedecarboxylase (ODC). The citrulline-NO pathway is catalyzed by induced nitric oxide synthase (iNOS). Citrulline is also produced from carbamoylphosphate and ornithine. When ornithine is reduced through Arg-1 inhibition by nor-NOHA, homocitrulline is produced from carbamoylphosphate and lysine.

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Materials and Methods

Animals and treatments

Female NOD mice of around 8 weeks of age were purchased from Taconic Biosciences (USA) and Jackson Laboratories (USA) and housed in groups of five with access to food and water ad libitum. The room temperature was kept at 23°Celsius and the light-dark cycle was 12/12 hours. All animal procedures were approved by the IACUC of the University of Miami. Nor-NOHA was obtained from Cayman Chemicals (USA). It was dissolved in PBS (phosphate buffered saline), and injected intraperitoneally at the dose of 30mg/kg every other day until 12 doses were completed. Blood sugar measurements were obtained using Contour Next® glucometer and strips (Bayer). A drop of blood was obtained by pricking the distal end of the tail with a 25G hypodermic needle and the drop was applied to the blood glucose strip. Non-fasting blood sugar levels were measured every two days before and during the treatment period (with nor-NOHA or PBS), and then once in the week after, and once 172 days after the beginning of the treatment. Mice were considered diabetic after 3 consecutive readings of hyperglycemia (>300mg/dL) [7].

Metabolomics analysis

Blood concentration data for arginine, its derivatives, and other metabolites used here were obtained in an untargeted metabolomics study by LC–MS as described previously in detail [9]. In brief, repeated blood samples were collected prospectively from NOD mice at 6, 11, 16, 21, and 26 weeks of age. Blood glucose was also measured at least twice weekly to monitor diabetes incidence in the same mice. Data from blood samples obtained in mice that developed diabetes by 26 weeks of age were pooled into the diabetic (progressor) group, and those from mice remained normoglycemic by the same age were considered as non-diabetic controls (non-progressors) in the analysis. We did not conduct analysis in mice older than 26 weeks of age to avoid potential confounding issues related to long-standing diabetes and the insulin therapy in the diabetic mice. The metabolomics data in the diabetic mice (up to 26 weeks of age) were expressed as fold increase relative to nondiabetic controls. See reference [9] for complete details.

Statistical analysis

Data were plotted and analyzed using Prism 6 version 6.07 (GraphPad Software, Inc; La Jolla California USA). Kaplan-Meyer survival curves were used to calculate the median age (in weeks) of spontaneous onset of diabetes in the total pooled populations of female NOD mice obtained from the different vendors. Additional analysis of the median age of diabetes onset was also performed based on the cumulative percent of diabetic mice over time assuming a Hill-type sigmoidal dependence. Estimations of the incidence rate of diabetes was done with onset data binned per week and obtained using the slope values of linear regression analysis of the cumulative percent of diabetic mice in two different regimes using a rate-change point identified by a linearized biexponential model as previously described in detail [10,11]. Segmental linear regression analysis was carried out using the minimum sum of squared errors method to identify the change in inflection of the data (i.e., transition points between the linear regimes). The diabetes incidence rate or probability in each regime (i.e., the estimated number of mice developing diabetes during a specified age-range) was calculated based on the slope value multiplied by the age-range (in weeks) and divided by the total number of mice remaining normoglycemic at the beginning of the chosen age range. Comparisons of the slopes of the linear regressions was done by F-test. Pair-wise comparisons of the treatment groups were by Student t-test or ANOVA followed by post hoc tests (e.g., Holm-Sidak method). Data are presented as means±SEM. Asterisks indicate significant difference at p <0.05 level.

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Results

Changes in arginine metabolism in diabetic progressor vs. non-progressor female NOD mice

We assessed the metabolism of arginine and other amino acids as part of an untargeted longitudinal metabolomics study [9] in repeated blood samples obtained from female NOD mice that did or did not progress to autoimmune diabetes during a follow up period between 6 and 26 weeks of age. The overall results showed relatively similar metabolic profiles between the groups before onset of diabetes (i.e., between 6 and 16 weeks) (Figure 2). However, differences in arginine metabolites and other amino acids became evident between 21 and 26 weeks coincident with diabetes onset. At week 26, ornithine was reduced by ~30% and citrulline was elevated by ~20% in diabetic mice (D-NOD) compared to non-diabetic controls (ND-NOD) (Figure 2A). Lysine was also reduced by ~50% while homocitrulline was significantly increased at weeks 21 (50%) and 26 (110%) in diabetic mice compared to non-diabetic counterparts (Figure 2B).

Incidence of autoimmune diabetes in NOD mouse population as a function of age

We tracked the spontaneous incidence of autoimmune diabetes in a total pooled population of young female NOD mice (n=126) starting around 8 weeks of age. Mice that received no treatment started to develop diabetes around 10 weeks of age. By 38 weeks, approximately 80% of the mice became diabetic and the remaining 20% maintained normoglycemia up to ~43 weeks of age (Figure 3A). According to Kaplan-Meyer survival curve analysis, in this cohort the median age of diabetes onset was 19.9 weeks in the total population of female NOD mice aged up to 43 weeks. Further analysis of diabetes incidence based on the cumulative percentage of diabetic mice during the same age range using nonlinear regression analysis (fit with a Hill curve) showed a median age of diabetes onset of 17.8 weeks (Figure 3B). While these analyses yielded estimates of the age of diabetes onset in the total population between 8 and 43 weeks of age, they could not provide estimates of the likelihood of diabetes development in the remaining ~20% fraction of mice that maintained normoglycemia up to this age. Data indicate that, at least in these NODs, the rate of diabetes onset is not completely flattened out (i.e., zero), and there is a decreasing, but non-zero chance of still developing diabetes in older female NOD mice. Therefore, we adopted a multi-linear model to fit the data along two distinct linear regimes from 10 to 23 and 24 to 43 weeks of age with a rate-of-change point selected as to give the best fit of the data (Figure 3C) also see Methods). The slopes of the first and second regimes obtained this way (6.2 and 0.62, respectively) were significantly different (p<0.00001), which indicated varying diabetes incidence rates before and after 23 weeks of age in this pooled NOD mouse population.

The effect of nor-NOHA on the incidence of autoimmune diabetes in old NOD mice

Normoglycemic old female NOD mice were treated with nor-NOHA (30mg/kg, i.p.) or PBS as control every other day for 24 days starting around 45 weeks of age. During the treatment period, the non-fasting blood glucose levels in both treatment groups fluctuated but remained within “normal” glycemia range (<300mg/dL). During a 6-week follow up period, the mean non fasting glycemia (measured every 2 days) in the PBS-treated mice was higher on 8 occasions and lower on 7 occasions than in the nor-NOHA group (Figure 4A). While all mice remained normoglycemic during and after the treatment period, there was a tendency toward lower mean non-fasting glycemia in the nor- NOHA-treated mice compared to the PBS controls as indicated, for example, by the blood glucose AUC data (Figure 4B) and the median values of non-fasting blood glucose at selected time-points with marginally significant difference (Figure 4C). Moreover, further follow up of the mice up to 25 weeks after treatment initiation showed that 50% of the PBS-treated mice became diabetic, while 100% of the nor-NOHA-treated mice remained normoglycemic (Figure 4D).

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Discussion

Female NOD mice are used extensively as a model for human autoimmune T1D [12-17]. Numerous studies have shown that under specific-pathogen-free conditions typically 70-90% of female NOD mice develop diabetes spontaneously by 45 weeks of age [9,11]. Consistent with this, we found an 80% diabetes incidence rate in a population of 126 female NOD mice aged up to 43 weeks (Figure 1). While most studies are conducted in NOD mice that develop diabetes before this advanced age, the remaining 10–30% of NOD mice that maintain normoglycemia by age 45 weeks are typically discarded from studies because of their reduced incidence of diabetes. Histological analysis of the pancreas from these older non-diabetic female NOD mice have shown evident mononuclear cell infiltrate around relatively intact islets [11]. This observation, also known as peri-insulitis, raises the possibility for local immune regulatory processes that may slow down the autoimmune attack against the insulinproducing beta cells, leading to reduced diabetes incidence. It is unclear however what specific diabetes incidence rate old female NOD mice have because long-term follow up beyond 45 weeks of age is rarely done, likely due to experimental and other logistical considerations. We reasoned that old non-diabetic female NOD mice provide a useful model to investigate the effects of different interventions aimed at changing the incidence of autoimmune diabetes beyond the age range where the probability of diabetes onset is significantly higher due to more aggressive autoimmune responses against the beta cells. Studies in older non-diabetic NOD mice may also be more representative of immune processes in adults, and may be particularly pertinent to the investigation of immune regulatory function and immune tolerance.

Arginine metabolism has been implicated in both proinflammatory and immune regulatory processes. Consequently, alternate arginine metabolism through the ornithine or citrulline pathways may lead, respectively, to decreased or increased incidence of autoimmune diabetes (Figure 1). Proinflammatory Th1/Th17 cytokines activate iNOS which produces nitric oxide (NO) from L-arginine through the citrulline- NO metabolic pathway in proinflammatory immune cells. NOproducing immune cells such as M1 macrophages can damage the pancreatic islets during diabetes development (McDaniel et al., 1996). Citrulline is also produced from carbamoylphosphate and ornithine; however, when ornithine is less abundant homocitrulline is produced from carbamoylphosphate and lysine. While no significant variations of citrulline and ornithine levels in the blood have been reported in association with aging [18], homocitrulline has been shown to increase progressively with age and has been suggested as a biomarker of aging-associated inflammation [19,20]. Homocitrulline has also been implicated in the pathogenesis of autoimmune arthritis [21,22], but little is known about its involvement in T1D. Our current findings, however, showing significantly elevated homocitrulline levels in diabetic NOD mice (Figure 2B) suggest its possible involvement, in addition to arginine metabolism, in the inflammation during the pathogenesis of T1D, and this involvement is likely to have persisted in the mice aged beyond 26 weeks old. Alternatively, Th2 cytokines induce arginase-1, which hydrolyses arginine into urea and ornithine, and in turn drives immune cell polarization towards regulatory function. Ornithine is also a precursor for polyamines that are required for cell proliferation and maintenance (Classen et al., 2009). Consistently, our current findings showed increased levels of citrulline and reduced levels of ornithine in diabetic female NOD mice compared to nondiabetic counterparts (Figure 2A). Therefore, we investigated whether reducing ornithine through arginase-1 inhibition by nor-NOHA treatment and promoting the alternate argininecitrulline- nitric oxide (NO) pathway will influence the incidence of autoimmune diabetes in >45 weeks old female NOD mice.

Based on our analysis of the incidence of diabetes in female NOD mouse population, we estimated incidence rates of approximately 64% and 43% in mice aged 10 to 23 and 24 to 43 weeks, respectively. These predicted rates were consistent with those observed in the total NOD population for each of the age ranges (66% and 31%; Figure 3A). Using the same approach and by extrapolating the data in the second linear regime up to 68 weeks of age, we estimated that ~50% of the NOD mice remaining normoglycemic by age 43 weeks (i.e., 45 out of 126) will become diabetic by 68 weeks. Consistent with this predicted rate, our experimental data showed that half of the control PBS-treated mice became diabetic by 68 weeks of age (Figure 4D); whereas, unexpectedly, all the nor-NOHAtreated mice remained normoglycemic during the same follow up period. This was surprising because blocking the arginineornithine pathway makes arginine more available for the alternate arginine-citrulline-NO pathway, and was expected to increase NO production and associated pro-inflammatory effects causing increased diabetes incidence. Contrary to this, our current findings suggested that nor-NOHA treatment seemingly protected the mice from autoimmune diabetes. While more studies are needed to further explain these findings, and while we did not measure citrulline and other arginine metabolites and polyamines in the >45 weeks old mice, the current results are consistent with other studies using nor-NOHA in animal models of inflammatory conditions other than T1D. For instance, nor-NOHA was reported to ameliorate inflammation in (i) the adipose tissues of mice on a high-fat-diet [23], (ii) the bronchi in an animal model of bronchial asthma [24], and (iii) the arteries of another model of arthritis [25]. Therefore, while we speculate that arginase-1 inhibition in our study likely resulted in increased production of NO, the relatively short nor-NOHA treatment regimen we used may have resulted in moderate increase in NO levels, which has been shown to have anti-inflammatory rather than proinflammatory effects [3-5]. Moreover, nor-NOHA could have interfered with the production of the proinflammatory eukaryotic translation initiation factor 5A (eIF5A) to prevent the autoimmune response, as blocking eIF5a with siRNA was recently shown to reduce mouse mortality by LPS [26], and its knockdown increased resistance to streptozotocin-induced diabetes in mice [27]. Moreover, treatment with di-fluoromethyl-ornithine (DFMO; a blocker of ornithine decarboxylase which transforms ornithine into putrescine/hypusine) or with N1-guanyl-1,7-diaminoheptane (an inhibitor of the enzyme desoxyhypusine which is critical for the activation of eIF5A) was also shown to reduce insulitis and the incidence of autoimmune diabetes in young NOD mice [28,29]. Interestingly, the eIF5A inhibitor DFMO is currently in clinical trials to evaluate its effect on halting the progression of autoimmune diabetes in children with new onset T1D (Clinical Trials.gov; study identifier NCT02384889).

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Conclusion

In summary, our current study showed that arginine metabolism is altered in diabetes-prone NOD mice; the arginine-citrulline-NO pathway was upregulated, whereas the alternate arginine-ornithine pathway was downregulated in diabetic female NOD mice as compared to their non-diabetic counterparts. A 24-day treatment with the arginase-1 inhibitor nor-NOHA aimed to further upregulate the citrulline-NO pathway unexpectedly reduced the incidence of autoimmune diabetes in older diabetes-prone female NOD mice. These findings warrant further investigation of the mechanism of action of nor-NOHA on the autoimmune process in diabetes, and highlight its potential as a therapeutic agent for the treatment or prevention of T1D.

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[didanawisgi]

Microbiome Dependent Regulation of Tregsand Th17 Cells in Mucosa

[popebengtsen63]

The particular cerebral palsy genome depiction involving Adenium obesum: Gene articles, do it again corporation as well as phylogeny.

Two of Three or more together with inflamed illnesses acquired soften, concentric charter yacht wall membrane advancement. 3 of three using dissection confirmed brilliant signal about T1, and a couple of experienced unusual wall development with a flap and also dual lumen. Conclusions: Three-tesla contrast-enhanced MRI can be used to read the wall of intracranial arteries. T2 as well as precontrast and postcontrast T1 fluid-attenuated inversion recovery photographs in 3 tesla may be able to distinguish enhancement habits associated with intracranial atherosclerotic plaques (eccentric), irritation (concentric), as well as other wall structure pathologies. Future studies are forced to determine the particular awareness and also specificity associated with arterial wall structure photo pertaining to differentiating the plethora of pathologic situations influencing cerebral vasculature. Neurology (Ur) 2009; Seventy two:627-634Purpose of review It has become a longer lasting question in which though much the same side-line allergen-specific immune system reply has become observed, how come several people demonstrate just atopic eczema, rhinitis and also bronchial asthma on it's own or perhaps their own combinations? The solution resides within the tendency regarding resident muscle tissue and native antigen-presenting cellular material as well as Big t cellular material pertaining to building a good sensitive inflamation related resistant result. Antigen-presenting tissue bring in processed substances to T helper lymphocytes, when a choice of establishing different types of Capital t mobile health emerges consuming numerous cytokines, chemokines, costimulatory indicators and regulating T tissues. Recent findings We targeted within this evaluate article on effector T cellular subsets, which have been just lately explained such as Th9, Th17 tissue and also Th22 tissue, that happen to be characterized by their particular IL-9 and also IL-10, IL-17 ( or IL-17A) and also IL-22 expression, correspondingly and various other proinflammatory cytokines, which usually coordinate community cells inflammation. The two naturally occurring CD4+CD25+ regulation Capital t (Treg) tissue and inducible populations of allergen-specific, IL-10-secreting Treg variety One particular tissue slow down allergen-specific effector cells and possess been demonstrated to experience a central role from the buy Tozasertib repair of side-line homeostasis along with the business involving controlled defense answers throughout sensitized inflamation related cells. Summary Better knowing along with portrayal regarding fresh defined effector mobile subsets in addition to their discussion in between antigen delivering tissues and also person tissue tissue will certainly illuminate our knowledge on the mechanisms associated with sensitized diseases.All of us explain a primary posterior capsulotomy approach utilizing a 25-gauge vitreous second hand cutter to avoid postoperative rear supplement opacification (PCO) inside sufferers with vitreoretinal illnesses that have to have a vitrectomy along with cataract surgical treatment. Pursuing phacoemulsification, the 25-gauge vitrectomy, along with intraocular contact implantation in the capsular handbag, the posterior pill is slowly removed with a pars plana method employing a 25-gauge vitreous cutter machine; the actual removed capsule is rounded, well centered, and around Five.0 millimeters across. This technique stops postoperative PCO totally, enhancing perspective and enabling thorough study of the fundus soon after surgical treatment.

[tannerbentsen]

Belief and also Use of Reason for Care Products: Any Cross-sectional Study Targeting Residents as well as Trainers inside Oman.

8-10, 95% CI Is equal to 2.66-0.Ninety-seven) and also a significant association had been witnessed among both of these teams(OR Equates to A single.44, 95% CI = One particular.1-1.99, g Equates to 0.021). No factor inside bloodstream group (A-, B+, B-, O+, O-, as well as AB-) has been seen involving situations as well as regulates. It does not take 1st document associated with an connection among HTLV-1-infected sufferers and also ABO/Rh bloodstream teams in our novels evaluate. Each of our outcomes might claim that the actual Any + blood class limit the risk of HTLV-1 infection inside healthy settings, while the Stomach + blood vessels class is more regular in HTLV-1 carriers UAMC-3203 research buy along with increases the probability of HTLV-1 disease.Acute denial is still a major reason behind first graft reduction and a danger aspect pertaining to long-term recipient post-transplant success. Recently, CD4(+)CD25(+)Foxp3(+) regulation Capital t (Treg) cellular material along with Th17 cellular material are already referred to as two distinct subsets together with opposition effects on autoimmunity and transplant immunity. We investigated the presence of Th17/Treg practical disproportion in between patience and being rejected groupings during rat hard working liver hair loss transplant. After that, Th17/Treg capabilities on several amounts ended up looked into comparatively in between the two organizations, including linked cytokine secretion and also essential transcription factors. REJ teams unveiled substantial rise in Th17-related cytokine (IL-17, IL-6 and IL-23) and transcription aspect (ROR gamma big t) ranges and remarkable reduction in Treg-related cytokine (IL-10 and TGF-beta One particular) along with transcription factor (Foxp3) quantities in comparison with day-matched TOL groupings coming from evening Several post-transplantation. Results mentioned Th17/Treg functional discrepancy in between building up a tolerance and also negativity groupings through rat liver organ hair transplant, recommending any part of Th17/Treg imbalance throughout pathogenesis associated with serious implant negativity. (H) Next year Elsevier B.Versus. Almost all protection under the law reserved.Glioblastoma treatment method as today constituted delivers increased survival measured within weeks more than without treatment individuals. Simply because glioblastomas are active in synthesizing a massive variety of progress aspects, a planned out way of suppressing these kind of will be undertaken since treatment adjunct. The particular serotonin 6 receptor can be commenly overexpressed throughout glioblastoma. Research documents showing agonists at this receptor 6 lead to increased extracellular regulated kinase 1/2 account activation, elevated interleukin-6 synthesis, elevated sign transducer as well as activator involving transcription-3 initial, elevated effectiveness against apoptosis as well as other growth improving modifications in glioblastoma will be reviewed with this papers. Due to the fact three drugs throughout wide employ to deal with believed disorders -- paliperidone, pimozide and risperidone - are also powerful and well-tolerated inhibitors with serotonin receptor 7, these kind of drugs ought to be researched for growth issue deprivation within an adjunctive position inside glioblastoma remedy.All of us to begin with describe a singular tRNA-derived SINE household, generously along with arbitrarily distributed inside the genome with the baseball bat Pipistrellus kuhli. Many of us found facts that this Collection retrotransposition machines will be recruited for the creation of a fresh chimerical retrotranscript constituted from the part Series invert transcriptase ORF2, which can be cut off with the SINE 16 retrotransposon. Structurel homology among SINE 20 and also Homo sapiens helix 6 7SL RNA we can suggest a number of genome spouses for SINE retrotransposition, for example SRP meats and also Series enzymatic machinery.

[qgbhj45698]

扁桃體菌群免疫調節作用被證實！或可用于治療類風濕關節炎

扁桃體是重要的淋巴器官，因其産生的淋巴細胞和抗體，可以對付入侵的各種致病微生物（包括細菌、病毒、寄生蟲等），發揮著抗細菌、抗病毒的防禦功能，常常被稱爲是人體免疫系統的第壹道大門。

近日，北京大學人民醫院臨床免疫中心栗占國教授課題組和中國科學院微生物所王軍教授課題組合作，在Advanced Science在線發表論文“Tonsillar microbiome-derived lantibiotics induce structural changes of IL-6 and IL-21 receptors and modulate host immunity”，證明了扁桃體菌群具有免疫調節的重要作用以及唾液鏈球菌抗菌肽Salivaricin在類風濕關節炎（RA）中發揮的免疫調節機制。通俗來講，當扁桃體抗菌肽不足時，可引發免疫反應紊亂。只要補充足夠的扁桃體抗菌肽，就可以避免免疫反應的發生或用于類風濕關節炎等自身免疫病的治療。

必利勁副作用 必利勁購買 必利勁哪裡買 必利勁價錢 必利勁服用方法 必利勁ptt 必利勁藥局 必利勁藥房 必利勁台灣官網 Dapoxetine 必利勁作用

這是國際上首次針對類風濕關節炎患者及正常人扁桃體菌群的研究，爲自身免疫疾病的治療提供了潛在靶點。

口咽部是飲食和呼吸的必經之路，因此扁桃體存有豐富的微生物，其中不僅存在有益菌，也含有致病菌。當受到氣候、環境、飲食等外界刺激或自身免疫力較弱之時，就會出現扁桃體微生態失調（常見的細菌、病毒感染），引發局部免疫激活而誘發全身免疫反應，如溶血性鏈球菌感染可引發風濕熱和急性腎小球腎炎。

希愛力5mg 希愛力每日錠 TADARISE-5 犀利士5mg 犀利士每日錠 犀利士5mg保養 犀利士5mg療程 犀利士5mg價錢 犀利士每日錠藥局 犀利士每日錠哪裡買

臨床上可以見到，扁桃體發炎會導致RA的發生（扁桃體免疫異常與RA發病密切相關），患者關節滑膜中的致病性T細胞可能來源于扁桃體，但扁桃體參與RA發病的作用機制尚不清楚。爲此，栗占國課題組關注了扁桃體菌群在類風濕關節炎發病中的作用及機制。

作者通過提取患者和正常人扁桃體菌群，采用宏基因組測序方法，發現RA患者扁桃體菌群明顯異常；再通過宏基因組數據分析得出，來自唾液的Salivaricin（是壹種能抵禦細菌、真菌或病毒等微生物入侵的抗菌肽），它的基因豐度顯著減少，而外周血中促炎免疫細胞，如前體濾泡輔助性T細胞（pTfh） 、樹突狀細胞（DC）以及漿細胞的比例卻明顯增加。通俗的講，就是當扁桃體內的有益菌減少，致使抗菌能力大大降低，不能控制周邊的炎症反應，造成感染或免疫反應的發生。必利吉 P-force 必利吉哪裡買 必利吉效果 希愛力 印度希愛力 希愛力功效 希愛力雙效片 希愛力價格 希愛力20mg

在進壹步的體外細胞實驗中，研究人員證實Salivaricin可特異性抑制Tfh細胞（濾泡輔助性T細胞）的分化和活化，而對外周血中促進炎症反應的細胞Th1，Th17和Treg（調節性T細胞）無明顯影響。

此外，該研究還發現Salivaricin通過與促炎細胞因子IL-6（白細胞介素-6）和IL-21受體結合阻斷IL-6/IL-21- JAK-STAT3信號通路的激活，抑制自身免疫反應，來預防和治療實驗性關節炎。希愛力 印度希愛力 超級希愛力 希愛力功效 希愛力副作用 希愛力價格 希愛力雙效片 希愛力40mg

[dancerdenim7]

Regulation of the KDihydrotestosterone-JNK difference junction signaling path simply by immunomodulator astragaloside IV attenuates neuropathic discomfort

For most wild types afflicted with unique pests or bad bacteria, the actual comparable significance about heritable genetic variants determining apparent deviation throughout disease level of resistance is unidentified. This is correct in particular pertaining to butternut, the North American real wood affected by butternut canker ailment and starting group contraction. Tiny is known concerning web site results #Link# in butternut fall, simply because long-term checking information do not have. Many of us gathered in depth condition phenotypes and also multilocus microsatellite genotypes for those enduring individuals in the large natural inhabitants involving butternut within 2004 (n=302) along with The coming year (n=113). A couple of systematic methods, connections between pairwise phenotypic similarity as well as pairwise relatedness, along with calculate regarding among-family deviation, the two mentioned vulnerable heritability of disease-related qualities and no heritability regarding overall tree wellness in the population. Moreover, the investigation of spatial files collected throughout Late 2001 (n=341) and also This year (n=113) established that less wet, upland web sites help with increased probability of emergency. Many of us determine in which anatomical variations amid wild butternut individuals added tiny for you to seen deviation inside emergency over Ten years but fine-scale web site variances were useful predictors associated with butternut fatality.People in the actual nuclear receptor superfamily function as transcribing aspects involved with inbuilt and also flexible health as well as lipid fat burning capacity. These highly protected protein take part in ligand-dependent or perhaps -independent regulation mechanisms affecting gene phrase. Peroxisome proliferator-activated receptors (PPARs), such as PPAR leader, PPAR beta/delta, and also PPAR gamma, are a number of nuclear receptor proteins that enjoy varied roles inside cell differentiation, growth, as well as metabolic rate. Every PPAR subfamily is initialized by different endogenous and artificial ligands. Recent surveys employing distinct ligand therapies and also cellular type-specific PPAR ko these animals get unveiled crucial functions of these healthy proteins inside T-cell-related auto-immune ailments. Furthermore, PPARs have been shown to regulate T-cell success, activation, along with CD4(+) T associate cell difference into the Th1, Th2, Th17, as well as Treg lineages. The following, all of us #Link# evaluate the reports that provide insight into quite regulating functions of PPARs throughout T-cell activation, survival, growth, difference, along with auto-immune illness.The actual n-6 essential fatty acid arachidonic chemical p (Alcoholics anonymous; 30:4n-6) brings about eicosanoid mediators which have founded functions in infection as well as Alcoholics anonymous fat burning capacity is really a lengthy recognised targeted for commonly used anti-inflammatory treatments. It's got usually been believed that all AA-derived eicosanoids tend to be pro-inflammatory. However this is a good over-simplification since several activities involving eicosanoids are usually anti-inflammatory (e.grams. prostaglandin (PG) Electronic(Two) prevents production of a number of inflammatory cytokines) and it has recently been discovered quite not too long ago which PGE(Two) suppresses output of inflamation related leukotrienes and also triggers production of infection managing lipoxin Any(Four). The n-3 efas through oily sea food along with "fish oils", eicosapentaenoic acidity #Link# (Environmental protection agency; 20:5n-3) along with docosahexaenoic acidity (DHA; Twenty-two:6n-3), are generally incorporated into inflamed mobile or portable phospholipids in the time- along with dose-dependent manner.

[melodyegypt65]

Caramboxin alternatively Antiplatelet Remedy within Heart People Non-Sensitive for you to Discomfort

Smear has additionally been proven to hole for you to mRNA cap analogs as well as depurinate mRNA downstream from the limit structure. The particular natural function regarding hat presenting and it is achievable function in PAP activity are not known. Ideas display the very first primary quantitative evidence regarding Smear presenting for the cap analog michael(Several)GTP. All of us statement the binding affinity of 43.Three +/- Zero.One particular nM at 25 levels D since dependant on fluorescence quenching studies. This really is exactly like the ideals described regarding whole wheat cap-binding proteins elFiso4E along with elFiso4F. van't Hoff analysis of meters(Seven)GTP-PAP stability discloses a presenting reaction that is certainly enthalpy driven along with entropy favored together with Capital t Delta Azines diplomas surrounding 15% to the overall price of Delta H certifications. This really is contrary to your whole wheat cap-binding protein that happen to be enthalpically pushed inside the Delta H degrees pertaining to presenting. Competition #Link# findings indicate that ATP as well as GTP remain competitive for the cap-binding site about Smear using a bit different affinities. Fluorescence scientific studies involving PAP-elFiso4G binding disclose the protein-protein discussion having a Okay(deb) regarding 108.Some +/- 2.3 nM. elFiso4G has been consideration to boost the interaction associated with Smear together with michael(7)GTP cover analog through Two.4-fold. These types of final results propose the actual effort of PAP-translation start issue things inside RNA choice and depurination. (H) 2009 Elsevier B.V. Just about all privileges set aside.MALDI-TOF (Matrix Assisted Laser Desorption Ionization-Time regarding Flight)-mass spectrometry has become employed, for the first time, within the study #Link# associated with entire Bifidobacterium cells-host goal proteins discussion. Particularly, by using this method, a dosage reliant human being plasminogen-binding action has been shown with regard to Bifidobacterium. The particular engagement of lysine binding web sites on the microbe mobile or portable floor has become turned out. The particular attained outcome is discovered being consistent with #Link# which via well-established regular techniques, therefore the actual suggested MALDI-TOF method can key in as a quick alternative technique in biorecognition studies experiencing microbe cellular material along with proteins associated with man beginning. (Chemical) 2009 Elsevier W.Sixth is v. Almost all protection under the law set aside.Throughout restoration from lymphopenia, the actual unsuspecting T-cells go through homeostasis influenced spreading (HDP) and have any recollection phenotype. The actual HDP involving T-cells requires indicators produced by T-cell-receptor, p56lck kinase, IL-7R as well as IL-15R. Nevertheless, the function involving some other signaling substances during HDP associated with CD4+ T-cells remains assuming. The difference of naive T-cells directly into Th1/Th2/Th17 or even Treg populations in the course of HDP isn't nicely realized. Existing record explains the particular spatial along with signaling traits involving HDP associated with CD4+ T-cells in addition to their cytokine information. The HDP involving CD4+ T-cells was found to take place simply within specific areas (T-cell zones) involving extra lymphoid internal organs regarding lymphopenic rats.

[partycast1]

Tankyrase inhibitor Apilimod increases osteoblastogenesis and also mineralization involving human being skeletal (mesenchymal) come cells

Furthermore, mRNA expression associated with interleukin ()-12, the Th1-associated cytokine, has been lacking in MN people in comparison to ANCAGN along with MPGN individuals. In comparison, an extremely greater expression associated with IL-4 as well as IL-5 has been noticed in MN compared to ANCAGN and MPGN people. In the studies associated with Th17-associated cytokine phrase, a significantly higher phrase involving IL-6 along with IL-17 ended up being seen in ANCAGN when compared to MPGN along with Minnesota individuals. No substantial variances have been noticed in the actual phrase of the cytokines among MPGN along with MN patients. With regard to Treg-associated cytokines, a lot larger IL-10 appearance ended up being affecting MN than in ANCAGN individuals, along with a significantly larger altering progress factor-beta expression had been seen in MN than in ANCAGN along with MPGN patients. Likewise, Foxp3 phrase has been drastically increased inside Minnesota. Conclusion:Th1 along with Th17 resistant reactions in ANCAGN, the particular Th1 reply in MPGN, as well as Th2 and also Treg reactions in MN people may be crucial for the specific histological top features of these illnesses. Copyright laws (C) The year 2013 Azines. Karger AG, BaselSolution albumin, C-reactive proteins (CRP), along with the intima-medial thickness of the common carotid artery (CA-IMT) tend to be linked to specialized medical results in hemodialysis (HD) patients. Nevertheless, that is still not clear which in turn guidelines will be more reliable as predictors of long-term fatality #Link# . We all measured serum albumin, CRP, and CA-IMT inside 206 High definition sufferers younger as compared to Eighty years outdated, along with followed them for one more A decade. 100 sixty-eight sufferers (age group: 57 +/- 11 a long time, moment on High-definition: 12 +/- 7 years) have been going to the looks at. We separated most sufferers directly into a few tertiles according to their particular albumin ranges, and also conducted multivariate analyses to analyze the effect upon 10-year mortality #Link# . Seventy-three (43.5%) individuals had expired through the follow-up. Serum albumin ended up being drastically reduced the expired individuals compared to the making it through people (Three or more.8 +/- 2.Three vs. Four.Zero +/- Zero.Three, S < Zero.02), although CRP (Some.Seven +/- 5.3 versus. 2.8-10 +/- Three.5 #Link# g/L, P=0.09) and also CA-IMT (Zero.70 +/- Zero.20 as opposed to. 2.Fifty nine +/- 0.14 mm, G < 2.09) have been significantly higher inside the expired party. The multivariate evaluation says there was a significantly the upper chances for total fatality rate within Hi-def individuals with solution albumin < Three or more.8 g/dL (probabilities percentage Five.Apr [95% CI: 1.30-19.60], P=0.02) in comparison with those with albumin > Four.One particular g/dL. In comparison, CRP and also CA-IMT didn't accompany total loss of life. It makes sense from all of these conclusions that serum albumin is a lot more outstanding like a fatality forecaster compared with CRP along with CA-IMT in HD sufferers.This short article details a new prosthetically-driven standard protocol for your rehab with the completely edentulous maxillary posture utilizing immediate embed positioning and loading tactics.

[biomedscis]

The Effect of Multiple Sclerosis (MS) on Central Nervous System (CNS): OAJBS Publishers

The Effect of Multiple Sclerosis (MS) on Central Nervous System (CNS) by Ali Ahmadi* in Open Access Journal of Biomedical Science (OAJBS) 

Multiple sclerosis (MS) is an autoimmune disorder of the CNS in which myelin components are specifically targeted by the immune system and lead to the destruction of myelin axons and associated debilitating symptoms [1-3]. Also, according to studies, no effective treatment for this disease has been found. Therefore, a safe and effective treatment option for MS is needed. Also, the central nervous system (CNS) is separated from the immune system by a blood-brain barrier and is traditionally considered “immune system protection”, and immune cells are also able to target the brain and lead to CNS autoimmune disorders Pahan et al. [4]. An article measuring the effects of cinnamon on MS mice used cinnamon and the brown bark of the cinnamon tree, which has been used as a spice or flavouring around the world for centuries. In addition, medieval physicians used cinnamon for medical purposes to treat a variety of disorders such as osteoarthritis, cough, hoarseness, sore throat, etc. Also, according to the findings of various articles, the results show that widespread inflammation, Loss of regulatory T cells (Tregs), autoimmune Th1 and Th17 cell hyperactivity, failure of the cerebral blood-brain barrier (BBB) and blood-spinal cord barrier (BSB), and loss of light-protective molecules in the CNS are some of the symptoms that Demystifying manifestations are required in MS [1-3]. https://biomedscis.com/fulltext/the-effect-of-multiple-sclerosis-ms-on-central-nervous-system-cns.ID.000358.php

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[foodhealthsolutions]

Allicin regulates Treg/Th17 balance in mice with collagen‐induced arthritis by increasing the expression of MEKK2 protein

In this work, we clearly discuss allicin had effects to improve collagen‐induced arthritis by regulation Treg/Th17 balance.

Abstract

To study the role of Allicin in regulating Treg/Th17 ratio in splenic lymphocyte by increasing the expression of MEKK2 protein in MAPK signaling pathway, and to explore the mechanism of immune response in mice with collagen‐induced arthritis (CIA). Mouse CIA model was induced by chicken collagen type II, and experimental mice were randomly divided into NC group, Model group, and Allicin group. HE staining was used to compare the degree of joint pathological damage in mice of each group, and Masson staining to observe the proliferation of collagen tissue in each group. Flow cytometry detected Treg/Th17 ratio in splenic lymphocytes. Furthermore, RT‐PCR and WB were used to detect the mRNA and protein expression of related transcription factors and inflammatory factors Foxp3, ROR‐γt, and IL‐17A, as well as MEK2 protein expression in splenic lymphocytes. The results showed that Allicin treatment could reduce the severity of arthritis and the proliferation of collagen fibers on the surface of cartilage and bone joints in CIA mice. Compared with NC group, Treg decreased and Th17 increased in spleen lymphocyte of Model group (p < .01); after Allicin treatment, Treg increased while Th17 decreased significantly (p < .01). Meanwhile, MEKK2 protein expression in spleen lymphocyte of Model group decreased compared to that in NC group (p < .01), and MEK2 protein expression increased significantly after Allicin treatment (p < .01). To sum up, the present study suggests that MEKK2 protein plays an important role in the pathogenesis of CIA model. In terms of mechanism, Allicin may play a therapeutic role in rheumatoid arthritis (RA) by increasing the expression of MEKK2 protein and affecting Treg/Th17 ratio.

By: Yuling Zhang, Yufang Gong Title: Allicin regulates Treg/Th17 balance in mice with collagen‐induced arthritis by increasing the expression of MEKK2 protein Sourced From: onlinelibrary.wiley.com/doi/10.1002/fsn3.2034?af=R Published Date: Wed, 07 Apr 2021 23:34:49 -0700

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