Astragaloside IV (AS-IV) is the most active monomer in the traditional Chinese herbal medicine Radix Astragali, which has a wide range of antiviral, anti-inflammatory, and anti-fibrosis pharmacological effects, and shows protective effect in acute lung injury. This study utilized the immunofluorescence, flow cytometry, ELISA, RT-qPCR, Western blot and Hematoxylin and eosin(H&E) staining methods to investigate the mechanism of AS-IV in reducing viral pneumonia caused by influenza A virus (IAV) in A549 cells and BALB/c mice. The results showed that AS-IV suppressed ROS production in influenza virus-infected A549 cells in a dose-dependent manner, and subsequently inhibited the activation of NLRP3 inflammasome and Caspase-1, decreased IL-1β and IL-18 secretion. In BALB/c mice infected with Poly (I: C), oral administration of AS-IV can significantly reduce Poly (I: C)-induced acute pneumonia and lung pathological injury. Which provides a new therapeutic strategy for influenza virus infection.

Background: For a long time, the prevailing viewpoint suggests that shorter telomere contribute to chromosomal instability, which is a shared characteristic of both aging and cancer. The newest research presented that T cell immune deficiency rather than chromosome instability predisposes patients with short telomere syndromes to some cancers. However, the relationship between genetically determined telomere length and immune cells remains unclear. Methods: The two-sample Mendelian randomization (MR) analysis was conducted to elucidate the potential causal relationship. The genetic data of telomere length and the quantity of lymphocytes were obtained from the Genome-Wide Association Study. The inverse variance-weighted method was used to estimate the effects primarily and another four methods were as a supplement. Relevant sensitivity analysis was used to test the results. Results: The IVW method showed a significant correlation between telomere length and the percentage of T lymphocytes (OR: 1.222, 95% CI: 1.014-1.472, P = 0.035), indicating that short telomere length significantly increases the risk of low T cell percentage. Further analysis of T cell subsets indicated that shorter telomere length may primarily lead to a lower proportion of Natural Killer T cells (OR: 1.574, 95% CI: 1.281-1.935, P < 0.001). Analysis of B cell subsets revealed that shorter telomere length may be associated with a higher proportion of Naive-mature B cells, and a lower proportion of Memory B cells. And the sensitivity analysis indicated the validity and robustness of our findings. Conclusion: In summary, a causal relationship existed between telomere length and the quantity and differentiation of immune cells. Specifically, genetically predicted shorter telomere length was found to increase the risk of occurrence of immunosuppression and immunodeficiency.

Objectives:The purpose of this study was to examine the proportion of CD161 on CD56+Natural Killer(NK) cells in peripheral blood of primary Sjögren’s syndrome(pSS) and investigate its clinical relevance of pSS. Methods:The proportion of CD56+NK cells and CD161 on CD56+NK cells was detected by flow cytometry in 31 pSS patients and 29 healthy controls (HCs). The correlations between proportion of CD161+CD56+NK cells and clinical features and disease activity of pSS were further analysed. Meanwhile, we drew the receiver operating characteristic(ROC) curve to evaluate the diagnostic value of CD161+CD56+NK cells in pSS. Results: The proportion of CD56+ NK cells and CD161+CD56+NK cells decreased markly in pSS patients compared to HCs. The correlation analysis showed that proportion of CD161+CD56+NK cells negatively correlated with WBC,IgA,IgM,IgG,ESSRPI and ESSDAI,and positively correlated with complement C4.The proportion of CD161+CD56+NK cells in pSS patients with decayed tooth, fatigue, arthralgia, skin involvement, primary biliary cirrhosis(PBC),interstitial lung disease(ILD), anti-SSA/Ro60 positive, anti-SSB positive and high IgG was lower than that in negative patients. Furthermore, compared with innactive patients,the proportion of CD161+CD56+NK cells decreased obviously in active patients. The area under the curve(AUC)was 0.7375(P=0.0016),the results indicated that CD161+CD56+NK cells had certain diagnostic value for pSS. Conclusion: This study suggested that the proportion of CD56+NK cells and CD161+CD56+NK cells decreased significantly in pSS patients,and the proportion of CD161+CD56+NK cells negatively associated with the clinical features and disease activity of pSS patients. The CD161+CD56+NK cells may present as a potential target for therapy and a biomarker of disease activity in pSS .

Introduction: Bmal1 is an important circadian rhythm gene, and its effect on sepsis has not been entirely elucidated. The aim of this work was to explore the regulatory role and molecular mechanism of BMAL1 in sepsis. Methods: C57BL/6J mice and THP-1 macrophages were used to establish sepsis models in vivo and in vitro, respectively. The peritoneal macrophages (PMs) and liver Kupffer cells (KCs) of mice were extracted, and the expressions of BMAL1 and PGC-1α in various macrophages were detected by Western blotting and RT-qPCR. Overexpression of BMAL1 in macrophages with plasmid. Knocked down the expression of PGC-1α by short hairpin RNAs (shRNA). STL1267 is an inhibitor of BMAL1, was used to inhibit the expression of BMAL1 in mice. Western blotting was used to detected the expression of BMAL1 in macrophages. ELISA was used to detected the levels of imerleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in cell supernatant and mouse serum, and HE staining was used to detected the pathological changes of organs. In addition, we detected the mutual regulation of BMAL1 and PGC-1α. Results: Both the sepsis models in vivo and in vitro, the protein and mRNA expression of BMAL1 in macrophages were significantly decreased. Overexpression of BMAL1 inhibits LPS-mediated inflammatory response and promotes M2-type polarization of macrophages. Inhibition the expression of BMAL1 by STL1267 further aggravated the inflammatory reaction and multiple organ damage in septic mice. PGC-1α is the downstream factor of BMAL1. After silencing PGC-1α, the inhibitory effect of BMAL1 on inflammatory response of macrophages was significantly weakened. Conclusions: BMAL1 is a key factor in inhibiting macrophage inflammatory response and sepsis, and its molecular mechanism closely related to the regulation of BMAL1 to PGC-1α.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by hyperglycemia. T2DM is caused by various etiologies. The functional expansion of pancreatic β-cells is unable to compensate for the degree of insulin resistance (IR), resulting in a relative insulin deficiency. The onset and progression of T2DM are influenced by multiple variables, including genetics, lipid excess, oxidative stress, and inflammation. A growing body of research suggests that the components of the immune system are altered in T2DM. This suggests that T cell-mediated adaptive immunity stimulates inflammation and IR through the redistribution of cytokines, chemokines, and different T cell subsets. Metabolic inflammation is a central aspect of obesity, T2DM, and comorbidities. This review focuses on adaptive immune T cells, particularly CD4+ T cells, and examines the roles and effects of different helper T (Th) 1, Th2, Th17, Th22, and regulatory T cells (Tregs) in T2DM. Evidence for T cell activation and exhaustion in T2DM remains controversial and requires further investigation.

Abstract In the present study, the in vitro and in vivo anti-acne activation by flavonoid combination therapy were investigated, and the role and relationship between flavonoid and FOXO3 signaling pathway were discussed. Three natural flavonoid such as quercetin, kaempferol, luteolin had certain anti-inflammation activity. Meanwhile, the combination therapy significantly outperforming using these flavonoids alone, which might be attributed to the synergistic bactericidal effect on the cells. Besides, it was also found that the FOXO3 pathway play an important role in P acnes induced skin inflammation. It’s promoted the decreasing of FOXO3 signaling pathway activation and induced an increasing in sebum secretion. During the acne inflammatory response, the expression of pro-inflammatory cytokine was increased significantly. After flavonoid combination therapy, the pro-inflammatory cytokines expression levels such as TNF-α (19.36 ± 2.44 pg/ml), IL-8 (1392.52 ± 131.75 pg/ml), IL-1β (13.42 ± 4.54 pg/ml) and IL-6 (109.64±13.34 pg/ml) were significantly reduced. Flavonoid combination therapy effectively decreased the expression of pro-inflammatory cytokines and increased the secretion of the anti-inflammatory cytokines. In addition, the activation of the FOXO3 pathway was found to be inversely proportional to the expression of pro-inflammatory cytokines. In this study, the flavonoid combination therapy demonstrated a “synergistic effect” inhibiting the inflammatory process via the activation of the FOXO3 pathway. The enhanced synergy observed surpassed their individual effects when used in combination. Consequently, the “synergistic effect” of three flavonoid ingredients suggested a new approach for the development of anti-acne reagents as FOXO3 enhancers.

Hydatid disease is a rare tapeworm infection that can cause the formation of cysts in the liver and other organs. Although it is uncommon for patients to have both hydatid cysts and cancer at the same time, it is possible, and this can easily be confused with metastasis. Proper management of hydatid cysts in a patient with cancer requires the consensus of oncologists, hematologists, and infectious disease specialists. According to a literature review and investigation of case reports, the treatment approach depends on the stage of the cyst, and chemotherapy management remains unchanged. It is crucial to follow specific treatment guidelines for each stage of the cyst to ensure proper treatment.

The intestinal mucosal immune system is a specialized immune system that interacts closely with commensal microorganisms. The intestinal mucosal tissues are characterized by the way they generate immune responses to pathogens. The symbiotic flora in turn regulates the host's mucosal immunity, maintaining a dynamic balance. The disruption of the equilibrium between the two can result in intestinal disorders. This paper summarises in depth the relationships between the two and serves as a resource for future research.

Recently we demonstrated that in 452 COVID-19 inpatients higher colchicine doses reduced the mortality about 5 times. Here we report another 333 cases of COVID-19 inpatients, treated with different doses of colchicine. There was a clear trend of reduction in the mortality of inpatients with increasing doses of colchicine between 2- and 7-fold. Colchicine loading doses of 4 mg are more effective than those with 2 mg. Despite higher than the so-called “standard doses” of colchicine, our doses are completely safe. The World Health Organization (WHO)-recommended strategy to inhibit viral replication had partial success because there is no direct link between viral load and the hyperactivation of the NLRP3 inflammasome. The neutralization of the IL-6 effects with anti-receptor antibodies and the inhibition of the tyrosine kinase JAK can be compromised if NLRP3 continues to be hyperactive and generates a cytokine storm. Our treatment strategy to inhibit the SARS-CoV-2 entry into the cell with inhaled bromhexine and the hyperactivated NLRP3 inflammasome with higher doses of colchicine, as the source of the cytokine storm practically solves the problem of treating COVID-19. The timing of initiation of treatment is critical.

Background: autoimmune diseases (ADS) are associated with sepsis. This study aims to investigate the causalities between ADs and sepsis using Mendelian randomization (MR). Methods: we extracted single-nucleotide polymorphisms (SNPs) closely associated with 10 ADs, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), type 1 diabetes (T1D), multiple sclerosis (MS), inflammatory bowel disease (IBD), celiac disease (CD), psoriasis (PsO), primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), and ulcerative colitis (UC) from the GWAS. Two-sample MR analysis was conducted using GWAS data from the UK Biobank to assess the association between the liability of each ad and sepsis and sepsis-related 28-day mortality. The inverse variance-weighted (IVW) method was used as the primary analysis. If sig-nificant causal relationships are found (considering multiple comparisons) in the univariate MR analysis, multivariate MR (MVMR) analysis is performed to adjust for body mass index (BMI) and smoking. A series of sensitivity analyses were conducted to validate the robustness of the results. Results: after adjusting for multiple testing, MR analysis revealed that PSC patients are responsible for increased susceptibility to sepsis using the IVW method (OR:1.033, 95%CI:1.007-1.060, PFDR = 0.020). Further sensitivity analyses validated the robustness of the above association. Even after adjusting for BMI and smoking, the MVMR-IVW still displayed a positive correlation（OR:1.043, 95%CI:1.022-1.064, P-value for IVW = 3.32E-05） between PSC patients and susceptibility to sepsis. However, no significant causal relationship was observed between SLE, RA, T1D, MS, IBD, CD, PsO, PBC, and UC with susceptibility to sepsis or short-term death risk. Conclusions: our MR analysis revealed a genetic susceptibility of PSC to sepsis. However, no causal relationship was observed between SLE, RA, T1D, MS, IBD, CD, PsO, PBC, and UC with suscep-tibility to sepsis or short-term death risk. Keywords: autoimmune diseases; sepsis; primary sclerosing cholangitis; Mendelian randomization

There are few accurate prognostic indications of the illness’s development and severity for COVID-19, despite certain biomarkers having been investigated. The unexpected nature of COVID-19’s course, which can quickly progress from asymptomatic to severe disease, lies at the heart of the disease’s intricacy. Predicting SARS-CoV-2 pathogenicity through laboratory biomarkers and as such, identifying the patients’ illness severity at the time of initial admission would be crucial in aiding patient care. In this study, we sought to evaluate hematological, biochemical and inflammatory biomarkers in COVID-19 patients. This was a cross-sectional research with 48 COVID-19 patients (16 asymptomatic/mild, 16 moderate, and 16 severe) and 48 age-sex matched COVID-19-negative clients from Moi Teaching and Referral Hospital in Kenya. On admission, demographic information, symptoms, and laboratory test results were collected. Significantly, COVID-19 severity was associated with hemoglobin (p<0.0001), white blood cells (p=0.0022), hematocrit (p<0.0001), blood urea nitrogen (p=0.01), blood sodium (p=0.0002), potassium (p=0.0483), C-reactive protein (p=0.0002), and Lactate Dehydrogenase (p<0.0001). CRP showed a high positive connection (0.5433; p=0.0006) with COVID-19 severity, but LDH showed a mild positive correlation (0.2484; p<0.0001). When comparing asymptomatic/mild COVID-19 to severe COVID-19, discriminative accuracy for CRP and LDH was greatest (AUC:0.8867, 95% CI:0.7532-1.000) and (AUC:1.000, 95% CI:1.000-1.000), respectively. Inflammatory biomarkers, hematological and biochemical indices have the potential to complement SARS-CoV-2 testing and predict the course of COVID-19. This will be useful in designing appropriate care for COVID-19 patients through targeted therapy.

The SARS-CoV-2 immune response is crucial for disease management, although diminishing immunity raises the possibility of reinfection. In matched samples collected at one month and six to eight months after infection, we examined the immunological response to SARS-CoV-2 in a group of convalescent critically ill COVID-19 patients. The PBMCs were isolated from enrolled study participants and flow cytometry analysis was done to assess the lymphocyte subsets of naive, effector, central memory, and effector memory CD4+ or CD8+ T cells in COVID-19 patients at one month and six to eight months after infection. Immunophenotypic characterization of immune cell subsets was performed on individuals who were followed longitudinally for one month (n=44) and up to 6-8 months (n=25) after recovery from COVID infection. We observed that CD4+ T cells in hospitalized SARS-CoV-2 patients tended to decrease, whereas CD8+ T cells steadily recovered after one month, while there was a sustained increase in the population of effector T cells and effector memory T cells. Furthermore, COVID-19 patients showed persistently low B cells and a small increase in the NK cell population. In conclusion, our findings show that T cell responses were maintained at 6-8 months after infection. This opens new pathways for further research into the long-term effects in COVID-19 immunopathogenesis.

Drug abuse is a universal phenomenon that happens across the world. And the neurotoxicity caused by drug abuse in the central nervous system has been extensively studied during the last decade. More recently, the role of drugs causing neuroinflammation, which would subsequently affect dopaminergic neurotoxicity, has aroused wide attention. This paper aims to present a literature review of the studies on the role of the interleukin family in substance-dependent neuroinflammation. Currently, the most studied cytokines in the interleukin family in the drug field are IL-1 and IL-6. In addition, based on the previous literature on changes in interleukin in neuroinflammation induced by different drugs, this paper identifies neuroinflammation-related diseases caused by interleukin families, and summarizes recent advances in the dynamics, mechanisms, immunomodulatory and anti-inflammatory effects that are related to the pathogenesis of these diseases. In conclusion, this review elucidates substance-dependent neurotoxicity from the perspective of interleukin alterations.

Aim: Sepsis is associated with brain injury and acute brain inflammation, which can potentially transition into chronic inflammation, triggering a cascade of inflammatory responses that may lead to neurological disorders. Minocycline, recognized for its potent anti-inflammatory properties, particularly within the brain, was investigated in this study for its protective effects against sepsis-induced brain injury. Methods: Adult male C57 mice received pretreatment with varying doses of minocycline (12.5, 25, and 50 mg/kg) three days before sepsis induction. An intraperitoneal injection of 5 mg/kg LPS was used to induce sepsis. Spontaneous locomotor activity (SLA) and weight changes were assessed over several days post-sepsis to monitor the recovery of the mice. The expression of inflammatory mediators and oxidative stress markers was assessed 24 h post sepsis. Results: Septic mice exhibited significant weight loss and impaired spontaneous locomotor activity. Initially, minocycline did not attenuate the severity of weight loss (1 day) or locomotor activity impairment (4 hours post-sepsis), but it significantly accelerated the recovery of the mice in later days. Sepsis led to elevated mRNA expression of IL-1β and TNF-α, increased MDA levels, and decreased thiol content and SOD activity 24 hours after sepsis induction. Minocycline dose-dependently mitigated brain inflammation and oxidative stress damage. Conclusion: Our findings demonstrate that pretreatment with minocycline has the potential to prevent brain tissue damage and accelerate recovery from sepsis in mice, suggesting that minocycline may serve as a promising therapeutic intervention to protect against sepsis-induced neurological complications.

YAP/TAZ are two homologous transcriptional coactivators that promote cell proliferation, stem cell maintenance, and tissue homeostasis. Activated YAP/TAZ reflects the “social” behavior of cells, including cell adhesion and mechanical signals that cells receive from tissue structures and the surrounding extracellular matrix (ECM). Simultaneous activation or overexpression of YAP/TAZ has been shown to lead to cellular transformation and tumor development. Intestinal diseases are mostly inflammatory and tumor-based, and YAP/TAZ plays an important role in this process. However, many roles of the YAP/TAZ in the course of intestinal disease are not clear. Therefore, this paper discusses the YAP/TAZ-binding proteins, involved pathways, and related pathological processes in the development of inflammatory bowel disease and intestinal cancer disease.

Cow’s milk protein allergy (CMPA) in Latin America is little studied. We conducted a prospective study in 64 patients with a median age of 3 months, 39/64 (60.94%) were male, 23/64 (35.93%) had malnutrition, 56/64 (87.5%) had familiar atopy, 34/64 (51.56%) were receiving exclusive breastfeeding (EBF). The patients passed a medical evaluation by the specialist and underwent: Prick Test, ImmunoCAP, Fecal Calprotectin (FC) and fecal eosinophil derived neurotoxin (EDN), double-blind placebo control oral food challenges (DBPCFC) and were observed for one year regarding their clinical evolution and acquisition of tolerance. 58/64 (90.63%) had gastrointestinal manifestations, 7/64 (10.94%) had a dermatological manifestation, 2/64 (3.1%) had respiratory manifestations and 2/64 (3.1%) had anaphylaxis. 6/64 (9.38%) had an IgE - mediated CMPA. In patients with Non - IgE Mediated CMPA, fecal calprotectin was found to have a median of 284 mg/dL and an interquartile range (IQR) of 138.5 - 415.5. EDN had a median of 508.5 mg/dL with an IQR of 160.25 - 868. One year after diagnosis, the median FC decreased significantly with p < 0.0001. Malnutrition after one year was reduced to 17.18%. Likewise, 52/64 (81%) acquired tolerance after practicing DBPCFC on them. 33/64 (52%) used nutritional replacement formulas from the time of diagnosis, those who used Nutramigen LGG 15/16 (94%) acquired tolerance after practicing DBPCFC while 12/17 (71%) of those who used other formulas acquired tolerance (p. 0.08). Our findings are a good starting point for future studies that explore the diagnosis, acquisition of CMPA tolerance, and the use of hypoallergenic formulas with the particularities of our region.

(1)Background: This study employs bibliometric methods to comprehensively understand the fundamental structure of research about Autism Spectrum Disorder (ASD) Signaling Pathways by examining key indicators such as nations, institutions, journals, authors, and keywords.(2) Methodology: We utilized the WoScc database to retrieve literature relevant to ASD Signaling Pathways. Through visual analysis and tools like CiteSpace and VosViewer, we explored nations, institutions, journals, authors, and keywords, thereby constructing relevant networks.(3) Results: The study encompasses 1396 articles, revealing a consistent increase in publications. The United States, China, and Germany are leading nations in this literature. Regarding research institutions, the University of California system and Eric Klann have garnered significant attention due to their substantial contributions to the field of ASD Signaling Pathways. Most relevant research is published in the journal “Molecular Autism.” Research interests are concentrated across various themes, including “elevating neuronal β-catenin levels,” “Tunisian children,” “FMR1 gene knockout mice,” “de novo mutations,” “autistic children,” “local translation,” “propionic acid-induced mouse models,” “neurosystems,” “glucose metabolism,” and “neuronal migration.” Future research may emphasize exploring aspects such as gut microbiota, genes, stress, maternal immune activation, memory, and neurodevelopmental disorders of ASD.(4) Conclusion: This study, through bibliometric analysis of key indicators such as nations, institutions, journals, authors, and keywords, provides a comprehensive overview of the current state of research on ASD Signaling Pathways.

Interleukin-22 (IL-22) is an important cytokine in the intestinal environment. IL-22 is mainly produced by immune cells and targeted at non-immune cells such as epithelial and stromal cells in a broad array of tissues such as -but not restricted to- the liver and adipose tissue. IL-22 therefore connects immune functions with metabolic functions of the host, and since it is induced by the microbiota, connects host functioning to the outside environment. IL-22 induces epithelial cell proliferation aiding in rapid epithelium regeneration and wound healing. Additionally, IL-22 activates anti-apoptotic genes and DNA damage response pathways, enhancing epithelial cell survival. Recently, it has also been shown that IL-22 induces Paneth cell differentiation in humans. However, IL-22 can also contribute to intestinal epithelium damage and reduces microbial diversity in the intestine directly or indirectly by inducing excessive antimicrobial peptide production by epithelial cells. Moreover, IL-22 enhances angiogenesis and may therefore support tumorigenesis in the intestine. In conclusion, it appears that whether IL-22 has a beneficial or harmful effect in the mammalian intestine largely depends on its regulation. This review aims to provide a comprehensive overview of the current literature and emphasizes that IL-22 signalling outcome depends on the timing and duration of IL-22 production, the presence of it regulators such as IL-22BP, and the specific location of the cytokine production in the gastrointestinal tract.