Production Of Tumor Necrosis Factor Research Articles

Cancer Moonshot: Moonshot as a Magic Code to Guide Successful Solutions of Tough Challenges Such as Cancer

Presidential projects deal with monumentally important issues. Moonshot and war on cancer were two unrelated presidential projects: the moonshot project was successful, but the war on cancer project was unsuccessful. President Biden brought up these two presidential projects on Sept. 12, 2022 apparently with an intention to urge the health profession to learn from the success of moonshot to come up solutions to save 50% of cancer patients in the following 25 years. The goal of cancer moonshot was modest. The health profession, however, must make a drastic change on the approach of cancer therapy to fulfill cancer moonshot. Moonshot was an extremely difficult challenge. So far, the USA was the only nation able to achieve this difficult challenge. Evidently, the right approach to a difficult challenge was the magic code to the success of moonshot. On the other hand, a wrong approach to a simple matter might result in making simple problem unsolvable. Apparently, war on cancer was such a case. Cytotoxic chemotherapy and radiotherapy based on the killing of cancer cells were the choice of cancer establishments to wage the war on cancer. The approach was wrong, because cancer was a disease due to wound unhealing. Creating more wounds definitely was a wrong approach. The war on cancer was loomed to fail on the day of its declaration. The wrong approach continued to dominate cancer therapies with no hope in sight to successfully saving cancer patients. Cancer moonshot was in essence a protest of the failure to save cancer patients from the highest government official to the health profession. A change of approach on cancer therapy is obviously needed to save cancer patients. Since cancer is caused by wound unhealing. Wound healing process is the most appropriate modality of cancer therapy. Wound healing comes naturally, because the nature creates chemo-surveillance to ensure perfection of wound healing. Wound healing requires the proliferation and the terminal differentiation of progenitor stem cells (PSCs). The success of wound healing depends on the efficient differentiation of PSCs to eliminate the symptom created by the wound. Chemo-surveillance plays such an important role to dictate the success of wound healing. Chemo-surveillance can be damaged under pathological conditions to produce tumor necrosis factor (TNF) to cause cachexia symptoms. Inability of PSCs to undergo terminal differentiation due to the collapse of chemo-surveillance then forces PSCs to evolve into cancer stem cells (CSCs) and then to progress to faster growing cancer cells (CCs). Obviously, cancer arises due to the collapse of chemo-surveillance. Restoration of chemo-surveillance with CDA formulations is, therefore, the right approach of cancer therapy. The wisdom of the nature beats the wisdom of cancer establishments on the issue of cancer.

Identification of a novel role for the immunomodulator ILRUN in the development of several T cell subsets in mice

Inflammation and lipid regulator with UBA-like and NBR1-like domains (ILRUN) is a protein-encoding gene associated with innate immune signaling, lipid metabolism and cancer. In the context of innate immunity, ILRUN inhibits IRF3-mediated transcription of antimicrobial and proinflammatory cytokines by inducing degradation of the transcriptional coactivators CBP and p300. There remains a paucity of information, however, regarding the innate immune roles of ILRUN beyond in vitro analyses. To address this, we utilize a knockout mouse model to investigate the effect of ILRUN on cytokine expression in splenocytes and on the development of immune cell populations in the spleen and thymus. We show elevated production of tumor necrosis factor and interleukin-6 cytokines in ILRUN-deficient splenocytes following stimulation with the innate immune ligands polyinosinic:polycytidylic acid or lipopolysaccharide. Differences were also observed in the populations of several T cell subsets, including regulatory, mucosal-associated invariant and natural killer. These data identify novel functions for ILRUN in the development of certain immune cell populations and support previous in vitro findings that ILRUN negatively regulates the synthesis of pathogen-stimulated cytokines. This establishes the ILRUN knockout mouse model as a valuable resource for further study of the functions of ILRUN in health and disease.

B-cell cytokine responses to Porphyromonas gingivalis in patients with periodontitis and healthy controls.

Cytokine-producing B cells play a well-established role in modifying immune responses in chronic inflammatory diseases. We characterized B-cell cytokine responses against periodontitis-associated bacteria in patients with periodontitis. Blood and saliva samples were collected from patients with periodontitis grade B (N=31) or grade C (N=25), and 25 healthy controls (HCs). Mononuclear cells were stimulated with Porphyromonas gingivalis, Fusobacterium nucleatum, Staphylococcus epidermidis, or Cutibacterium acnes, and B-cell production of tumor necrosis factor (TNF)-α, interleukin (IL)-6, interferon (IFN)-γ, IL-10 and transforming growth factor (TGF)-β by B cells was assessed by flow cytometry. HCs had higher baseline frequencies of B cells producing IFN-γ or TNF-α than grade B patients, but only B cells from grade B patients showed significant differentiation into IFN-γ-, TNF-α-, TGF-β-, or IL-10-producing cells after challenge with P. gingivalis and into IFN-γ-, TGF-β-, or IL-10-producing cells after challenge F. nucleatum. Notably, the baseline frequency of IL-10-producing B cells from grade C patients correlated inversely with clinical attachment loss (AL). The major proportion of the IFN-γ- and TGF-β-producing B cells were CD27+ memory cells, while the IL-10-producing B cells were mainly CD27- CD5- . B cells from grade B patients, particularly those harboring P. gingivalis, showed proinflammatory B-cell responses to P. gingivalis. Moreover, the baseline frequency of IL-10-producing B cells in the grade C group correlated inversely with AL, suggesting a diminished immunoregulatory capacity of IL-10-producing B cellsinthesepatients.

Streptolysin O Deficiency in Streptococcus pyogenes M1T1 covR/S Mutant Strain Attenuates Virulence in In Vitro and In Vivo Infection Models.

Mutation within the Streptococcus pyogenes (Streptococcus group A; Strep A) covR/S regulatory system has been associated with a hypervirulent phenotype resulting from the upregulation of several virulence factors, including the pore-forming toxin, streptolysin O (SLO). In this study, we utilized a range of covR/S mutants, including M1T1 clonal strains (5448 and a covS mutant generated through mouse passage designated 5448AP), to investigate the contribution of SLO to the pathogenesis of covR/S mutant Strep A disease. Up-regulation of slo in 5448AP resulted in increased SLO-mediated hemolysis, decreased dendritic cell (DC) viability post coculture with Strep A, and increased production of tumor necrosis factor (TNF) and monocyte chemoattractant protein 1 (MCP-1) by DCs. Mouse passage of an isogenic 5448 slo-deletion mutant resulted in recovery of several covR/S mutants within the 5448Δslo background. Passage also introduced mutations in non-covR/S genes, but these were considered to have no impact on virulence. Although slo-deficient mutants exhibited the characteristic covR/S-controlled virulence factor upregulation, these mutants caused increased DC viability with reduced inflammatory cytokine production by infected DCs. In vivo, slo expression correlated with decreased DC numbers in infected murine skin and significant bacteremia by 3 days postinfection, with severe pathology at the infection site. Conversely, the absence of slo in the infecting strain (covR/S mutant or wild-type) resulted in detection of DCs in the skin and attenuated virulence in a murine model of pyoderma. slo-sufficient and -deficient covR/S mutants were susceptible to immune clearance mediated by a combination vaccine consisting of a conserved M protein peptide and a peptide from the CXC chemokine protease SpyCEP. IMPORTANCE Streptococcus pyogenes is responsible for significant numbers of invasive and noninvasive infections which cause significant morbidity and mortality globally. Strep A isolates with mutations in the covR/S system display greater propensity to cause severe invasive diseases, which are responsible for more than 163,000 deaths each year. This is due to the upregulation of virulence factors, including the pore-forming toxin streptolysin O. Utilizing covR/S and slo-knockout mutants, we investigated the role of SLO in virulence. We found that SLO alters interactions with host cell populations and increases Strep A viability at sterile sites of the host, such as the blood, and that its absence results in significantly less virulence. This work underscores the importance of SLO in Strep A virulence while highlighting the complex nature of Strep A pathogenesis. This improved insight into host-pathogen interactions will enable a better understanding of host immune evasion mechanisms and inform streptococcal vaccine development programs.

Specialized pro-resolving lipid mediators regulate inflammatory macrophages: A paradigm shift from antibiotics to immunotherapy for mitigating COVID-19 pandemic.

The most severe clinical manifestations of the horrifying COVID-19 disease, that claimed millions of lives during the pandemic time, were Acute respiratory distress syndrome (ARDS), Coagulopathies, septic shock leading eventually to death. ARDS was a consequence of Cytokine storm. The viral SARS-COV2infection lead to avalanche of cytokines and eicosanoids causing "cytokine storm" and "eicosanoid storm." Cytokine storm is one of the macrophage-derived inflammatory responses triggered by binding of virus particles to ACE2 receptors of alveolar macrophages, arise mainly due to over production of various pro-inflammatory mediators like cytokines, e.g., interleukin (IL)-1, IL-2, and tumor necrosis factor (TNF)- α, causing pulmonary edema, acute respiratory distress, and multi-organ failure. Cytokine storm was regarded as the predictor of severity of the disease and was deemed one of the causes of the high mortality rates due to the COVID-19. The basis of cytokine storm is imbalanced switching between an inflammation increasing - pro-inflammatory (M1) and an inflammation regulating-anti-inflammatory (M2) forms of alveolar macrophages which further deteriorates if opportunistic secondary bacterial infections prevail in the lungs. Lack of sufficient knowledge regarding the virus and its influence on co-morbidities, clinical treatment of the diseases included exorbitant use of antibiotics to mitigate secondary bacterial infections, which led to the unwarranted development of multidrug resistance (MDR) among the population across the globe. Antimicrobial resistance (AMR) needs to be addressed from various perspectives as it may deprive future generations of the basic health immunity. Specialized pro-resolving mediators (SPMs) are generated from the stereoselective enzymatic conversions of essential fatty acids that serve as immune resolvents in controlling acute inflammatory responses. SPMs facilitate the clearance of injured tissue and cell debris, the removal of pathogens, and augment the concentration of anti-inflammatory lipid mediators. The SPMs, e.g., lipoxins, protectins, and resolvins have been implicated in exerting inhibitory influence on with cytokine storm. Experimental evidence suggests that SPMS lower antibiotic requirement. Therefore, in this review potential roles of SPMs in enhancing macrophage polarization, triggering immunological functions, hastening inflammation resolution, subsiding cytokine storm and decreasing antibiotic requirement that can reduce AMR load are discussed.

Oral administration of the commensal Alistipes onderdonkii prolongs allograft survival.

Intestinal commensals can exert immunomodulatory effects on the host, with beneficial or detrimental consequences depending on underlying diseases. We have previously correlated longer survival of minor mismatched skin grafts in mice with the presence of an intestinal commensal bacterium, Alistipes onderdonkii. In this study, we investigated its sufficiency and mechanism of action. Oral administration of A onderdonkii strain DSM19147 but not DSM108265 was sufficient to prolong minor mismatched skin graft survival through inhibition of tumor necrosis factor production. Through metabolomic and metagenomic comparisons between DSM19147 and DSM108265, we identified candidate gene products associated with the anti-inflammatory effect of DSM19147. A onderdonkii DSM19147 can lower inflammation both at a steady state and after transplantation and may serve as an anti-inflammatory probiotic beneficial for transplant recipients.

Aspergillus oryzae Fermentation Extract Alleviates Inflammation in Mycoplasma pneumoniae Pneumonia.

The filamentous fungus Aspergillus oryzae, also known as koji mold, has been used for centuries in the production of fermented foods in East Asia. A. oryzae fermentation can produce enzymes and metabolites with various bioactivities. In this study, we investigated whether A. oryzae fermentation extract (AOFE) has any effect on Mycoplasma pneumoniae (Mp) pneumonia. We performed solid-state fermentation of A. oryzae and obtained the ethanol extract. AOFE was analyzed by HPLC, and the major component was identified to be kojic acid. In vitro, AOFE suppressed Mp growth and invasion into A549 lung epithelial cells as determined by the gentamicin protection assay. AOFE treatment also suppressed Mp-stimulated production of tumor necrosis factor (TNF)-α and interleukin (IL)-6 at mRNA and protein levels in murine MH-S alveolar macrophages. In a mouse model of Mp pneumonia, Mp infection induced a marked pulmonary infiltration of neutrophils, which was significantly reduced in mice pre-treated orally with AOFE. AOFE administration also suppressed the production of proinflammatory cytokines and chemokines in the lungs. Collectively, our results show that AOFE has the potential to be developed into a preventive/therapeutic agent for Mp pneumonia.

Von Willebrand factor: from figurant to main character in the scene of inflammation

von Willebrand factor: from figurant to main character in the scene of inflammation

TNFR1 links TNF exocytosis to TNF production in allergen-activated RBL-2H3 cells

We previously reported that the maximal production of Tumor Necrosis Factor (TNF or TNFα) in antigen-activated RBL-2H3 cells (a tumor analog of mucosal mast cells) requires Munc13–4, a regulator of exocytic fusion. In this study, we investigated the involvement of various fusion catalysts in TNF production. We observed a strong correlation between the total TNF level and TNF exocytosis in RBL-2H3 cells. RT-qPCR shows that TNFR1 (TNF receptor 1) is the sole TNFR expressed in these cells, and that its transcription is upregulated upon allergen-mediated activation. Importantly, the addition of soluble TNFR1 inhibits antigen-elicited TNF production in a dosage-dependent fashion. Likewise, TNF production is diminished in the presence of TACE (TNFα Converting Enzyme) inhibitor KP-457, which prevents the generation of soluble TNF (sTNF). Together, these findings indicate that sTNF and TNFR1 function as autocrine agent and receptor respectively at the mast cell surface to boost TNF proliferation during allergic inflammation.

Pharmacology of orismilast, a potent and selective PDE4 inhibitor.

There remains an unmet need for oral medications that are safe and efficacious for long-term management of chronic inflammatory skin diseases (CISD). Inhibition of phosphodiesterase 4 (PDE4) can modulate a broad range of pro-inflammatory cytokines that play a major role in CISD pathogenesis. Orismilast is a second generation PDE4 inhibitor in clinical development for CISD treatment. The objective of this study was to examine the PDE4 enzymatic activity and anti-inflammatory effects of orismilast in vitro, ex vivo, and in vivo. The PDE1-11 enzymatic activity of orismilast was tested in vitro using a single concentration of 308 nM orismilast. The PDE4 selectivity and inhibitory potency was further examined in a radiometric assay. Orismilast was tested on human whole blood and human peripheral blood mononuclear cells (PBMC) to determine effects on its cytokine secretion and inhibition profile ex vivo. Orismilast was orally administered in a murine model of chronic oxazolone-induced ear skin inflammation. Ear thickness, a marker of inflammation, and inflammatory cytokines were analysed. Orismilast selectively inhibited PDE4 and demonstrated potent inhibition of PDE4B and PDE4D subtype splice variants in vitro. Orismilast inhibited whole blood and PBMC production of tumour necrosis factor α (TNFα), and the secretion of T-helper (Th)1 (TNFα and IFNγ), Th17 (IL-22 and IL-23), and Th2 (IL-4, IL-5, and IL-13) related cytokines in PBMC. In vivo, 10 and 30 mg/kg doses of orismilast significantly reduced ear thickness and inflammation markers (p < 0.0001, respectively). Orismilast displayed selective and potent PDE4 inhibition and broad-spectrum anti-inflammatory activity in several pre-clinical models. The results of the study support clinical development of oral orismilast as a novel treatment option for CISD including psoriasis, atopic dermatitis, and hidradenitis suppurativa.

Ursolic Acid Derivatives Down Regulate Inflammatory Mediators

Ursolic acid (UA) is being investigated due to its anti-inflammatory potential, and structural modifications can enhance its biological activities. The aim of this study was to evaluate the immunomodulatory effect of the ursolic acid derivatives (UAD) in macrophages and in the carrageenan-induced paw edema model. RAW264.7 cells were cultured in the presence or absence of UA or UAD (1-18). Nitric oxide (NO), nuclear factor kappa B (NF-κB), tumor necrosis factor (TNF), and cellular viability were measured. 30 min before the carrageenan-induced paw edema, the UAD1 and UAD2 (200 mg kg-1) were administered intraperitoneally. The results showed that UAD2-4, UAD7, UAD9-11 had half maximal inhibitory concentration (IC50) greater than 90 µM and were able to reduce NO, NF-κB and TNF production. Moreover, UAD1 and UAD2 reduced paw edema and IL-6 production. In conclusion, the results obtained demonstrated a variation in the response between the derivatives due to the chemical modifications, showing potential to reduce the inflammatory mediators, deserving further investigations.

Anti-Inflammatory Effects of the 35kDa Hyaluronic Acid Fragment (B-HA/HA35).

Hyaluronic acid (HA) and HA fragments interact with a variety of human body receptors and are involved in the regulation of various physiological functions and leukocyte trafficking in the body. Accordingly, the development of an injectable HA fragment with good tissue permeability, the identification of its indications, and molecular mechanisms are of great significance for its clinical application. The previous studies showed that the clinical effects of injectable 35kDa B-HA result from B-HA binding to multiple receptors in different cells, tissues, and organs. This study lays the foundation for further studies on the comprehensive clinical effects of injectable B-HA. We elaborated on the production process, bioactivity assay, efficacy analyses, and safety evaluation of an injectable novel HA fragment with an average molecular weight of 35 kDa (35 kDa B-HA), produced by recombinant human hyaluronidase PH20 digestion. The results showed that 35 kDa B-HA induced human erythrocyte aggregation (rouleaux formation) and accelerated erythrocyte sedimentation rates through the CD44 receptor. B-HA application and injection treatment significantly promoted the removal of mononuclear cells from the site of inflammation and into the lymphatic circulation. At a low concentration, 35 kDa B-HA inhibited production of reactive oxygen species and tumor necrosis factor by neutrophils; at a higher concentration, 35 kDa B-HA promoted the migration of monocytes. Furthermore, 35 kDa B-HA significantly inhibited the migration of neutrophils with or without lipopolysaccharide treatment, suggesting that in local tissues, higher concentrations of 35 kDa B-HA have antiinflammatory effects. After 99mTc radiolabeled 35 kDa B-HA was intravenously injected into mice, it quickly entered into the spleen, liver, lungs, kidneys and other organs through the blood circulation. This study demonstrated that the HA fragment B-HA has good tissue permeability and antiinflammatory effects, laying a theoretical foundation for further clinical studies.

Adenosine pathway regulates inflammation during Plasmodium vivax infection.

Plasmodium spp. infection triggers the production of inflammatory cytokines that are essential for parasite control, and conversely responsible for symptoms of malaria. Monocytes play a role in host defense against Plasmodium vivax infection and represent the main source of inflammatory cytokines and reactive oxygen species. The anti-inflammatory cytokine IL-10 is a key regulator preventing exacerbated inflammatory responses. Studies suggested that different clinical presentations of malaria are strongly associated with an imbalance in the production of inflammatory and anti-inflammatory cytokines. A convenience sampling of peripheral blood mononuclear cells from Plasmodium vivax-infected patients and healthy donors were tested for the characterization of cytokine and adenosine production and the expression of ectonucleotidases and purinergic receptors. Here we show that despite a strong inflammatory response, monocytes also bear a modulatory role during malaria. High levels of IL-10 are produced during P. vivax infection and its production can be triggered in monocytes by P. vivax-infected reticulocytes. Monocytes express high levels of ectonucleotidases, indicating their important role in extracellular ATP modulation and consequently in adenosine production. Plasmatic levels of adenosine are not altered in patients experiencing acute malaria; however, their monocyte subsets displayed an increased expression of P1 purinergic receptors. In addition, adenosine decreases Tumor Necrosis Factor production by monocytes, which was partially abolished with the blockage of the A2a receptor. Monocytes have a dual role, attempting to control both the P. vivax infection and the inflammatory response. Purinergic receptor modulators emerge as an untapped approach to ameliorate clinical malaria.

One-step preparation of boronic acid-rich hydrothermal spheres for N-glycopeptide analysis from preeclampsia serum.

In this study, we developed a green, one-step hydrothermal carbonization (HTC) method that used water as the sole solvent to create boronic acid group-rich carbonaceous spheres (BCS). When the abundant boronic acid groups on the carbonaceous spheres react with the hydroxyl groups on the glycans in an alkaline environment, the glycopeptides are specifically captured. The results showed that BCS had excellent detection limits (0.1 fmol μL-1), selectivity (1 : 1000), and stability (10 cycles). In addition, the BCS also demonstrated excellent glycopeptide enrichment capabilities in complex biological samples; 219 glycopeptides attributed to 167 glycoproteins and 235 glycopeptides related to 166 glycoproteins in PE patient and normal pregnancy control serum were identified by nano LC-MS/MS, respectively. In addition, the molecular function of heparin binding and biological process of complement activation, positive regulation of immune response, and positive regulation of tumor necrosis factor production were significantly different between PE patients and healthy pregnant women according to gene ontology analysis, indicating that these may be associated with the development of PE.

Spirulina platensis Suppressed iNOS and Proinflammatory Cytokines in Lipopolysaccharide-Induced BV2 Microglia.

The disease burden of neurodegenerative diseases is on the rise due to the aging population, and neuroinflammation is one of the underlying causes. Spirulina platensis is a well-known superfood with numerous reported bioactivities. However, the effect of S. platensis Universiti Malaya Algae Culture Collection 159 (UMACC 159) (a strain isolated from Israel) on proinflammatory mediators and cytokines remains unknown. In this study, we aimed to determine the anti-neuroinflammatory activity of S. platensis extracts and identify the potential bioactive compounds. S. platensis extracts (hexane, ethyl acetate, ethanol, and aqueous) were screened for phytochemical content and antioxidant activity. Ethanol extract was studied for its effect on proinflammatory mediators and cytokines in lipopolysaccharide (LPS)-induced BV2 microglia. The potential bioactive compounds were identified using liquid chromatography-mass spectrometric (LC-MS) analysis. Ethanol extract had the highest flavonoid content and antioxidant and nitric oxide (NO) inhibitory activity. Ethanol extract completely inhibited the production of NO via the downregulation of inducible NO synthase (iNOS) and significantly reduced the production of tumor necrosis factor (TNF)-α and interleukin (IL)-6. Emmotin A, palmitic amide, and 1-monopalmitin, which might play an important role in cell signaling, have been identified. In conclusion, S. platensis ethanol extract inhibited neuroinflammation through the downregulation of NO, TNF-α and IL-6. This preliminary study provided insight into compound(s) isolation, which could contribute to the development of precision nutrition for disease management.

Real-World Study of the Use of Iguratimod to Treat Chronic/Refractory ITP

Introduction: Immune thrombocytopenia (ITP) is an acquired, organ-specific, autoimmune disease and one of the most common bleeding disorders that seriously endangers human health. Iguratimod is a small molecule compound that is widely used as a novel antirheumatic drug in the treatment of rheumatoid arthritis in China and Japan. Iguratimod inhibits the production of several inflammatory cytokines, including IL-1, IL-6, IL-8, and tumor necrosis factor (TNF), and reduces the production of immunoglobulins. Th1 and Th17 cell counts were significantly reduced in patients with rheumatoid arthritis after treatment with iguratimod. The low long-term remission rate of ITP makes the investigation of its pathogenesis and the search for new treatments important clinical problems to be solved. Abnormal T-cell function and anti-platelet antibody production play important roles in the pathogenesis of ITP, and iguratimod is a therapeutic agent that could potentially be used to treat ITP. Previous clinical studies have shown that iguratimod can increase platelet levels in patients with dry syndrome. The potential of iguratimod for treating anti-platelet antibody-mediated thrombocytopenia in mice with ITP by modulating T-cell differentiation suggests that iguratimod may be a new approach for the prevention and treatment of ITP. Recent retrospective clinical studies and case reports have also shown that the use of iguratimod in autoimmune diseases is associated with good safety and efficacy. In conclusion, the aim of this study was to investigate the effect of iguratimod on the treatment of ITP. Methods: The study began in December 2020 and is ongoing. A total of 76 patients who were treated with iguratimod for at least 3 months were selected. Of these, 51 patients were treated for more than 6 months, and 30 patients were treated for at least 12 months. Five patients withdrew from observation after 3 months: two patients due to NR, three patients due to epidemic and financial reasons, and no patients due to AE. Key secondary endpoints included initial response by Day 14 (OR, platelet count ≥30×109/L, at least a 2-fold increase in baseline platelet count, and absence of bleeding; and CR, platelet count ≥ 100×109/L), duration of response, bleeding scores, and adverse events (AEs). This study was registered with ClinicalTrials.gov (). Results: At baseline, 73.5% of the patients reported symptoms of grade 1 to 4 bleeding. After 3 months of treatment, the proportion of patients with any bleeding symptoms decreased to 61.8% and remained below baseline throughout the study period. At baseline, 63 patients reported the use of concomitant medications, which decreased by 36.5% between 3 and 6 months. The most frequently discontinued or reduced medications were glucocorticoids and rituximab. All the patients took the medication in strict accordance with the instructions and medical advice. The patients were monitored monthly to assess blood, liver, kidney function, and no abnormalities in laboratory tests, such as elevated transaminases or lymphocytopenia, were observed. Conclusions: Iguratimod has good efficacy and safety in the treatment of ITP and has the potential to become a new treatment for ITP.

Anti-inflammatory activity of Echinosophora koreensis nakai root extract in lipopolysaccharides-stimulated RAW 264.7 cells and carrageenan-induced mouse paw edema model

Ethnopharmacological relevanceEchinosophora koreensis Nakai is an endemic plant species distributed in a limited area within the Korean province of Gangwon, including the Yanggu-gun, Inje-gun, Cheorwon-gun, Chuncheon-si, and Hongcheon-gun counties. It is used in traditional medicine to treat various disorders, such as fever, skin diseases, diuresis, and neuralgia. Materials and methodsThis study demonstrated the effects of E. koreensis Nakai root extract (EKRE) on lipopolysaccharide (LPS)-induced inflammatory responses in vitro and in vivo. Cell viability was assessed through a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Nitric oxide (NO) production was measured using Griess reagent. Interleukin (IL)-6 and tumor necrosis factor (TNF) levels were assessed using enzyme-linked immunosorbent assays. Inducible nitric oxide synthase (iNOS), nuclear factor kappa-B (NF-κB), and mitogen-activated protein kinase (MAPK) expression were assessed using Western blot analysis. To examine the effects of EKRE in vivo, it was administered orally at doses of 50 or 200 mg/kg for 3 days in mice. Edema in the paws was induced through λ-carrageenan injection and measured hourly for up to 5 h using calipers. ResultsEKRE markedly suppressed LPS-generated NO, IL-6, and iNOS production in RAW 264.7 cells. Moreover, it suppressed the activation of the NF-κB and MAPK in LPS-stimulated cells. Furthermore, EKRE significantly inhibited carrageenan-induced edema in mouse paws. There were no significant differences in IL-6 and TNF production in paw tissue harvested from mice, but levels decreased at high EKRE concentrations (200 mg/kg). ConclusionThe results of this study provided validation for EKRE-induced inhibition of inflammatory responses in vitro and in vivo. This research suggested that EKRE is a promising treatment for inflammatory disorders.

Preventive and therapeutic effect of bioactive component of licorice on antidepressant-induced liver injury

Since exploding rates of modern mental diseases, application of antidepressants has increased. Worryingly, the antidepressant-induced liver injury has gradually become a serious health burden. Furthermore, since most of the knowledge about antidepressant hepatotoxicity are from pharmacovigilance and clinical case reports and lack of observational studies, the underlying mechanisms are poorly understood and there is a lack of efficient treatment strategies. In this study, antidepressant paroxetine directly triggered inflammasome activation evidenced by caspase-1 activation and downstream effector cytokines interleukin(IL)-1β secretion. The pretreatment of echinatin, a bioactive component of licorice, completely blocked the activation. This study also found that echinatin effectively inhibited the production of inflammasome-independent tumor necrosis factor α(TNF)-α induced by paroxetine. Mechanistically, the accumulation of mitochondrial reactive oxygen species(mtROS) was a key upstream event of paroxetine-induced inflammasome activation, which was dramatically inhibited by echinatin. In the lipopolysaccharide(LPS)-mediated idiosyncratic drug-induced liver injury(IDILI) model, the combination of LPS and paroxetine triggered aberrant activation of the inflammasome to induce idiosyncratic hepatotoxicity, which was reversed by echinatin pretreatment. Notably, this study also found that various bioactive components of licorice had an inhibitory effect on paroxetine-triggered inflammasome activation. Meanwhile, multiple antidepressant-induced aberrant activation of the inflammasome could be completely blocked by echinatin pretreatment. In conclusion, this study provides a novel insight for mechanism of antidepressant-induced liver injury and a new strategy for the treatment of antidepressant-induced hepatotoxicity.

The Nurr7 agonist Cytosporone B differentially regulates inflammatory responses in human polarized macrophages

The orphan nuclear receptor Nur77 is involved in diverse cellular processes such as inflammation, proliferation, differentiation and survival. Stimuli like lipopolysaccharide (LPS) and tumor necrosis factor (TNF) increase Nur77 expression in human and murine macrophages, and it has been proposed that Nur77 plays a major role in dampening the inflammatory response. Here, we evaluated the expression and function of Nur77 in human anti-inflammatory and pro-inflammatory macrophages derived from blood monocytes cultured with macrophage colony-stimulating factor (M-MDMs) or granulocyte/macrophage colony-stimulating factor (GM-MDMs), respectively. Nur77 mRNA expression was significantly enhanced in M-MDMs compared with GM-MDMs, both constitutively and upon exposure to Toll-like receptor (TLR)2, 3, and 4 ligands. Nur77 activation with the agonist Cytosporone B (CsnB) significantly suppressed the production of TNF, interleukin (IL)-1β, IL-6, and IL-8 in GM-MDMs stimulated with LPS. In contrast, it tended to enhance the production of the anti-inflammatory cytokine IL-10. This effect was associated with reduced NF-κB p65 nuclear translocation. Similarly, Nur77 knockdown enhanced TNF production in GM-MDMs. CsnB effectively stimulated the transactivation activity of Nur77 in M-MDMs, but it did not alter cytokine synthesis or p65 nuclear translocation. However, Nur77 seemed to have a role in maintaining the anti-inflammatory profile of M-MDMs, since Nur77-deficient M-MDMs constitutively produced higher levels of TNF transcripts. Thus, in the absence of exogenous agonists, Nur77 activity favors the anti-inflammatory function of M-MDMs, whereas agonistic activation of this receptor preferentially drives attenuation of inflammation in inflammatory macrophages.

RNA sequencing reveals the transcriptome profile of the atopic prurigo nodularis with severe itching.

Prurigo nodularis (PN), characterized by inevitable chronicity and severe pruritus, is most frequently associated with atopy compared with other origins. However, the skin transcriptomic profiling of PN arising from atopic dermatitis (AD), so-called atopic PN (APN), remains unclear. We sought to explore the cutaneous transcriptome of APN with severe pruritus and compare it with classic AD. RNA sequencing was performed on the lesional skin from 13 APN to 11 AD patients with severe pruritus (itch numerical rating scale score ≥ 7) and normal skin from 11 healthy subjects. Quantitative real-time polymerase chain reaction and immunochemistry were used for validation. We detected 1085 and 1984 differentially expressed genes (DEGs) in lesional APN skin and lesional AD skin versus normal skin, respectively. In total, 142 itch/inflammation-related DEGs were identified. Itch/inflammation-related DEGs, such as IL-6, IL-10, IL-13, oncostatin M, and IL-4 receptor, had elevated gene transcript levels in both diseases. The itch/inflammation-related DEGs that increased only in APN were mainly neuroactive molecules, while many inflammatory mediators such as T helper 22-related genes were found to be increased only in AD. Both disorders showed mixed Th1/Th2/Th17 polarisation and impaired skin barrier. In contrast to AD, M1/M2 macrophage activation, tumor necrosis factor production, fibrosis, revascularization and neural dysregulation are unique features of APN. The study findings broaden our understanding of the pathogenesis underlying APN, which provides insights into novel pathogenesis with potential therapeutic implications.