Interleukin Research Articles

Evaluation of Inflammatory Status in COVID-19 Patients with Chronic Kidney Disease: A Comparative Analysis Based on Creatinine Clearance Levels

Background and Objectives: Patients with chronic kidney disease (CKD) are at increased risk of severe COVID-19 outcomes due to their compromised immune systems and chronic inflammatory state. This study aimed to evaluate and compare the inflammatory status of COVID-19 patients with CKD, stratified by creatinine clearance (CrCl) levels: CrCl < 30 mL/min, CrCl 30–60 mL/min, and CrCl > 60 mL/min. Multiple inflammatory scores combining laboratory parameters were assessed, including novel scores and established indices. Methods: In this retrospective cohort study, 223 patients admitted with confirmed COVID-19 were included and divided into three groups based on CrCl levels: CrCl < 30 (n = 41), CrCl 30–60 (n = 78), and CrCl > 60 (n = 104). Laboratory parameters including C-reactive protein (CRP), interleukin-6 (IL-6), neutrophil-to-lymphocyte ratio (NLR), ferritin, platelet count, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), and serum albumin were collected. Multiple inflammatory scores were calculated, including inflammation scores (IS1–IS4), the systemic inflammatory index (SII), the C-reactive protein-to-albumin ratio (CAR), the lymphocyte-to-C-reactive protein ratio (LCR), and the prognostic nutritional index (PNI). Statistical analyses were performed to compare inflammatory scores among groups and assess correlations with clinical outcomes. Results: The CrCl < 30 group exhibited significantly higher levels of inflammatory markers and inflammatory scores compared with the other groups (p < 0.001). Among the additional scores, CAR and SII were significantly elevated in patients with lower CrCl levels, while LCR and PNI were decreased. CAR showed a strong positive correlation with COVID-19 severity (r = 0.65, p < 0.001), and PNI was inversely correlated with mortality (r = −0.58, p < 0.001). Multivariate regression analysis indicated that lower CrCl levels, higher IS3 and CAR, and lower PNI were independent predictors of severe COVID-19 outcomes. Conclusions: CKD patients with lower CrCl levels have an amplified inflammatory response during COVID-19 infection, as evidenced by elevated inflammatory scores. The additional inflammatory scores, particularly CAR and PNI, may serve as valuable tools for risk stratification and management of COVID-19 in CKD patients. Early identification of patients with high CAR and low PNI could improve clinical outcomes through timely therapeutic interventions.

Interleukin-17A is a potential therapeutic target predicted by proteomics for systemic sclerosis patients at high risk of pulmonary arterial hypertension

We explored effective therapeutic targets for systemic sclerosis (SSc) patients with high risk for pulmonary arterial hypertension (PAH) by plasma proteomics analysis. A total of fifty-seven patients with SSc were enrolled in the study and the prevalence of PAH was 19.3%. On the other hand, 75.4% of SSc patients showed the ratio of forced vital capacity percentage/diffusing capacity of the lungs for carbon monoxide percentage> 1.6 and met criteria for high risk of PAH. Identification of elevated plasma proteins in SSc patients with high risk of PAH, followed by upstream regulator analysis, predicted interleukin (IL)-17A as a major upstream molecule. Furthermore, we performed in vitro neutralization study using MT-6194, a bispecific antibody targeting both IL-17A and IL-6 receptor. We found that MT-6194 broadly suppressed the increased expression of downstream molecules of IL-17A including IL-17A-related cytokines/chemokines, IL-17A-driven NF\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\kappa$$\\end{document}B pathway and IL-6-driven JAK/STAT pathway which were shown to be increased in SSc patients with high risk of PAH by the proteomics. Consequently, it is revealed that IL-17A is a promising target for early intervention in SSc patients with high risk for PAH.

Levocabastine ameliorates cyclophosphamide-induced hepatotoxicity in Swiss albino mice: modulation of Nrf2, NF-κB p65, cleaved caspase-3 and TGF-β signaling molecules.

Cyclophosphamide (CP)-induced hepatotoxicity is a significant problem in clinical settings. This study aimed to evaluate the protective effect of levocabastine (LEV) on CP-induced hepatotoxicity in Swiss albino mice. Mice were given CP (toxic drug) 200mg/kg, i.p., once on the 7th day, and LEV 50 and 100µg/kg, i.p., and fenofibrate (FF) 80mg/kg, p.o., daily for 14 days. On the 15th day, blood and liver samples were collected to assess biological parameters. CP 200mg/kg caused hepatotoxicity due to oxidative stress, inflammation, apoptosis, and fibrosis as manifested by a reduction in catalase, reduced glutathione (GSH), superoxide dismutase (SOD), and an increase in thiobarbituric acid reactive substance (TBARS), nitrite, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), transforming growth factor-beta 1 (TGF-β1), interleukin-1β (IL-1β), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) levels. Cleaved caspase-3 and nuclear factor kappa-B (NF-κB) expression was also increased and nuclear factor erythroid 2-related factor (Nrf2) expression was decreased as confirmed by Immunohistochemical analysis. It also caused histopathological abnormalities and fibrosis as manifested by Hematoxylin-Eosin (H&E) and Masson's trichrome (MT) staining. These alterations were returned to almost normal when treated with LEV 100µg/kg and FF 80mg/kg. Thus, LEV protected CP-induced hepatotoxicity by reversing inflammation, apoptosis, fibrosis, oxidative stress, hepatic injury, and histopathological damages. LEV can be helpful as an adjuvant in cancer patients who are on CP treatment, to minimize toxicity. However, its role in in-vivo cancer model is further needed to be confirmed.

Synergistic fermentation of Cordyceps militaris and herbal substrates boosts grower pig antioxidant and immune function

BackgroundPathogenic infections can significantly impact the health of livestock. Traditionally, antibiotic growth promoters (AGPs) have been used in feed to enhance growth performance and disease control. However, concerns regarding antibiotic resistance have led to the exploration of traditional herbal medicine as a natural alternative, guided by the principle of medicine-food homology. The Taguchi method was employed to optimize the culture formula for cordycepin production, an active component of Cordyceps militaris (C. militaris). The influences of C. militaris supplementing solid-state fermentation (CMSSF) in feed on the growth performance and immune responses of grower pigs were evaluated in the present study.ResultsThe C. militaris ethanol extract (CME) displayed potent free radical scavenging activity against 2, 2-Diphenyl-1-picrylhydrazyl (DPPH) and 2,2’-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) after undergoing fermentation. Additionally, the antibacterial testing revealed that CME effectively inhibits the growth of common pig pathogens such as Glaesserella parasuis, Pasteurella multocida, Staphylococcus hyicus, and Streptococcus suis. In lipopolysaccharide (LPS)-treated intestinal porcine enterocyte cell line (IPEC-J2), CME significantly suppressed the production of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-6. In addition, higher antioxidative activity was detected as indicated by elevated concentration of superoxide dismutase (SOD) in pig serum. The levels of immunoglobulin M (IgM), IgA, and IgG antibodies, as well as classical swine fever virus (CSFV) antibodies (S/P ratio) in serum were all increased. Growth performance of pigs fed with dietary CMSSF supplementation was improved in comparison with the control.ConclusionsResults demonstrated that CMSSF has the potential to be used as a natural growth promoter to enhance immunity, antioxidation, as well as overall health and growth performance of grower pigs.

Multi-targeted olink proteomics analyses of cerebrospinal fluid from patients with aneurysmal subarachnoid hemorrhage

BackgroundThe complexity of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) may require the simultaneous analysis of variant types of protein biomarkers to describe it more accurately. In this study, we analyzed for the first time the alterations of cerebrospinal fluid (CSF) proteins in patients with aSAH by multi-targeted Olink proteomics, aiming to reveal the pathophysiology of DCI and provide insights into the diagnosis and treatment of aSAH.MethodsSix aSAH patients and six control patients were selected, and CSF samples were analyzed by Olink Proteomics (including 96-neurology panel and 96-inflammation panel) based on Proximity Extension Assay (PEA). Differentially expressed proteins (DEPs) were acquired and bioinformatics analysis was performed.ResultsPCA analysis revealed better intra- and inter-group reproducibility of CSF samples in the control and aSAH groups. 23 neurology-related and 31 inflammation-relevant differential proteins were identified. In the neurology panel, compared to controls, the up-regulated proteins in the CSF of SAH patients predominantly included macrophage scavenger receptor 1 (MSR1), siglec-1, siglec-9, cathepsin C (CTSC), cathepsin S (CTSS), etc. Meanwhile, in the inflammation group, the incremental proteins mainly contained interleukin-6 (IL-6), MCP-1, CXCL10, CXCL-9, TRAIL, etc. Cluster analysis exhibited significant differences in differential proteins between the two groups. GO function enrichment analysis hinted that the differential proteins pertinent to neurology in the CSF of SAH patients were mainly involved in the regulation of defense response, vesicle-mediated transport and regulation of immune response; while the differential proteins related to inflammation were largely connected with the cellular response to chemokine, response to chemokine and chemokine-mediated signaling pathway. Additionally, in the neurology panel, KEGG enrichment analysis indicated that the differential proteins were significantly enriched in the phagosome, apoptosis and microRNAs in cancer pathway. And in the inflammation panel, the differential proteins were mainly enriched in the chemokine signaling pathway, viral protein interaction with cytokine and cytokine receptor and toll-like receptor signaling pathway.ConclusionsThese identified differential proteins reveal unique pathophysiological characteristics secondary to aSAH. Further characterization of these proteins and aberrant pathways in future research could enable their application as potential therapeutic targets and biomarkers for DCI after aSAH.

Association of gene polymorphism in ERG rs2836411 with anemia and susceptibility to aortic dissection

BackgroundThe erythroblast transformation-specific related gene (ERG) is expressed in hematopoietic stem and progenitor cells and endothelial cells. This study aimed to investigate if ERG rs2836411 is a novel genetic locus associated with anemia and aortic dissection (AD).MethodA case-control trial was conducted to evaluate the association between ERG rs2836411 polymorphism, anemia, and AD risk. The ERG rs2836411 polymorphism was analyzed using Sanger dideoxy chain termination sequencing on genomic DNA extracted from whole blood. Serum erythropoietin (EPO) and interleukin-6 (IL-6) concentrations were measured by enzyme-linked immunosorbent assay (ELISA).Results119 preoperative AD patients and 119 healthy controls were enrolled, with age and sex matched. Anemia was found independently associated with AD presence (Odds ratio (OR) 20.82, p < 0.001). Remarkably, T carriers (CT + TT) of ERG rs2836411 were associated with anemia in AD patients (OR 2.81, p = 0.013) but not in controls. After adjusting for conventional risk factors including age, sex, smoking and hypertension status, T carriers (CT + TT) were independently associated with AD presence (OR 2.20, p = 0.015), but were not associated if anemia was further adjusted. While EPO concentration was higher in AD patients and was associated with AD presence (OR 1.09, p = 0.006), no difference in EPO levels was observed between the ERG genotypes of AD patients.ConclusionsT carriers (CT + TT) of ERG rs2836411 are independently associated with anemia and AD presence. The association between ERG rs2836411 polymorphism and susceptibility to AD may be mediated by anemia. Further studies are warranted to validate whether this association is causal.

Hidradenitis Suppurativa: A Review of the Biologic and Small Molecule Immunomodulatory Treatments.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease that presents as painful, deep-seated nodules, sinus tracts, and abscesses in about 1% of the population. Although the pathogenesis of HS is not perfectly understood, it is generally recognized to be caused by a combination of genetic, endocrine, environmental, and microbiological factors. The treatment principles of HS focus on decreasing the microbial load with antibiotics and/or modulating the host immune response to reduce inflammation. The treatment of adults with moderate-to-severe HS has significantly changed recently with the development of new biological medications and immunomodulators. While previously the mainstay of treatment of moderate-to-severe HS was adalimumab, a biologic tumour necrosis factor α inhibitor, the evidence for the use of other treatment classes such as interleukin (IL)-17 inhibitors, IL-1 inhibitors, and Janus kinase inhibitors has been growing. The goal of this review article is to review the available evidence that supports the efficacy and safety of biologics and small molecule immunomodulator treatments to treat adults with moderate-to-severe HS.

Influence of blood trace elements on immune responses and adverse symptoms subsequent to Sinopharm COVID-19 vaccination

Trace elements, specifically magnesium (Mg), zinc (Zn), and selenium (Se) have been linked with immunomodulatory properties. This research delves into identifying the potential impression of serum levels Mg, Zn, and Se on the protective immunity arisen through Sinopharm COVID-19 vaccine in the vaccinated subjects. Levels of Mg, Zn, and Se, cytokine and antibody production as well as virus neutralization potency were investigated in 75 males and 75 females before and 2 weeks after first and second dose of vaccination. Level of Mg, Zn, and Se did not change significantly before and 2 weeks after first and second dose of vaccine administration. Concentrations of Interleukin (IL)-2, IL-6, and Interferon (IFN)-γ were significantly higher in the supernatant of peripheral blood mononuclear cells (PBMCs) obtained from subjects 2 weeks after both first and second dose of vaccination compared to before vaccination. Serum level IgG was significantly higher 2 weeks after first and second dose of vaccination compared to before vaccination. Serum level IgM was only higher after first dose of vaccination compared with before vaccine. Also, 2 weeks after both first and second dose of vaccination compared to before vaccination, FRNT50 titer was significantly higher. Levels of Mg, Zn, and Se did not significantly correlate with levels of IL-2, IL-6, IFN-γ, IgM and IgG, and FRNT50 after first and second dose of vaccination. No severe unwanted clinical symptoms were detected after vaccination. Mg, Zn, and Se do not play a role in modulating protective immunity during Sinopharm COVID-19 vaccine.

The significance of RB1 in multiple myeloma

The treatment of multiple myeloma (MM) has significantly advanced; however, the underlying genetic mechanisms remain elusive. Clonal events and genetic alterations are recognized as pivotal in the pathogenesis of MM. It is now understood that a multitude of gene mutations, including those affecting RAS, TP53, RB1, and 1q21 amplification, are prevalent in this disease. The incorporation of several high-risk genetic factors into the Second Revision of the International Staging System (R2-ISS) underscores the prognostic significance of genetic aberrations in MM. The retinoblastoma gene (RB1), located in 13q14, encodes the retinoblastoma protein (pRB), a tumor suppressor that regulates cell cycle progression. Deletion of RB1, which is a frequent event in MM, contributes to tumorigenesis by disrupting cell cycle control. In this respect, RB1 loss has been implicated in the progression of MM through its influence on interleukin-6 (IL-6) secretion and cell proliferation. This review comprehensively summarizes the role of RB1 in MM and expounds on the potential of targeting RB1 as a therapeutic strategy for this malignancy.

Paraoxonase-1 Is a Pivotal Regulator Responsible for Suppressing Allergic Airway Inflammation Through Adipose Stem Cell-Derived Extracellular Vesicles

Although adipose stem cell (ASC)-derived extracellular vesicles (EVs) are as effective as ASCs in the suppression of Th2 cell-mediated eosinophilic inflammation, the role of identified pulmonary genes has not been well documented. Thus, we assessed the immunomodulatory effects of paraoxonase-1 (PON1) on allergic airway inflammation in a mouse model of asthma. Five-week-old female C57BL/6 mice were sensitized to ovalbumin (OVA) by intraperitoneal injection and challenged intranasally with OVA. To evaluate the effect of PON1 on allergic airway inflammation, the intranasal and intraperitoneal injections of recombinant mouse serum PON1 (5 μg/50 μL) were performed before the OVA challenge. We evaluated airway hyperresponsiveness (AHR), total inflammatory cells, and eosinophils in the bronchoalveolar lavage fluid (BALF), lung histology, serum immunoglobulin (Ig), cytokine profiles of BALF and lung draining lymph nodes (LLNs), the expression of interleukin (IL)-25 and transforming growth factor (TGF)-β in mouse lung epithelial cell (MLE-12 cell), and dendritic cell (DC) differentiation. The intraperitoneal and intranasal administration of PON1 significantly decreased AHR, total inflammatory cells and eosinophils in BALF, eosinophilic airway inflammation, serum total, and OVA-specific IgE. PON1 treatment, which marked reduced IL-4, IL-5, and IL-13 in the BALF and LLN but significantly increased interferon-γ and TGF-β. Furthermore, PON1 treatment significantly decreased the expression of IL-25 and increased TGF-β in MLE-12 cells. The expressions of CD40, CD80, and CD86 in immature DCs were significantly increased by PON1 treatment. The administration of PON1 ameliorated allergic airway inflammation and improved AHR through the downregulation of IL-4, IL-5, and IL-13 and upregulation of TGF-β in asthmatic mice. Furthermore, PON1 treatment decreased Th2-mediated inflammation induced by Aspergillus protease antigen by decreasing IL-25 and increasing TGF-β.

Tissue-Specific DNA Methylation Changes in CD8+ T Cells During Chronic Simian Immunodeficiency Virus Infection of Infant Rhesus Macaques

Robust CD8+ T cell responses are critical for the control of HIV infection in both adults and children. Our understanding of the mechanisms driving these responses is based largely on studies of cells circulating in peripheral blood in adults, but the regulation of CD8+ T cell responses in tissue sites is poorly understood, particularly in pediatric infections. DNA methylation is an epigenetic modification that regulates gene transcription. Hypermethylated gene promoters are associated with transcriptional silencing and, conversely, hypomethylated promoters indicate gene activation. In this study, we evaluated DNA methylation signatures of CD8+ T cells isolated from several different anatomic compartments during pediatric AIDS-virus infection by utilizing the SIVmac239/251 infected infant rhesus macaque model. We performed a stepwise methylation analysis starting with total cellular DNA, to immunomodulatory cytokine promoters, to specific CpG sites within the cytokine promoters in CD8+ T cells isolated from peripheral blood, lymph nodes, and intestinal tissue during the chronic phase of infection. Tissue-specific methylation patterns were determined for transcriptionally active promoters of key immunomodulatory cytokines: interferon gamma (IFNγ), interleukin-2 (IL-2), and tumor necrosis factor alpha (TNFα). In this study, we observed tissue-specific differences in CD8+ T cell modulation by DNA methylation in SIV-infected infant macaques, highlighting the importance of evaluating cells from both blood and tissues to obtain a complete picture of CD8+ T cell regulation during pediatric HIV infection.

Estrogenized HSA induced high-affinity autoantibodies in breast cancer - Novel biomarker for early detection

ObjectiveBreast cancer (BC) is the second most prevalent cancer worldwide. Estrogen has been increasingly recognized as a major contributor to the development of BC, playing a more critical role than previously understood. Estrogen derived nucleic acid and protein adducts have been shown to play significant roles in BC development and progression. However, the alterations in molecular mechanism(s) and immune pathways arising as a result of estrogenization still remain elusive.Patients and methods4-hydroxyestradiol (4-OHE2) was used for adduct formation with protein human serum albumin (HSA) (4-OHE2-HSA). The affinity of antibodies for 4-OHE2-HSA was evaluated in breast cancer patients. Immunoassays (direct binding ELISA, inhibition ELISA, and quantitative precipitin titration assay) were used to assess autoantibodies against estrogenized HSA in BC patients (n = 85) and healthy controls (n = 45).ResultsEstrogenization of HSA altered both its structure and function and compromised its interactions with various HSA-binding proteins. BC patients demonstrated high-affinity antibodies against 4-OHE2-HSA as compared to HSA (p &amp;lt; 0.05). Additionally, cytokines Interleukin (IL)-1, IL-6 and tumor necrosis factor-alpha (TNF-α) were significantly elevated in BC patients as compared to the control group. Several factors, such as chemotherapy, estrogen receptors (ERs), and combination of surgery and chemotherapy, influenced the production of antibodies in cancer patients. The affinity constant for estrogenized HSA was 1.31 × 10-7 M, while for HSA and 4-OHE2, it was 1.68 × 10-6 M and 1.36 × 10-6 M, respectively.ConclusionsEstrogenized HSA is highly immunogenic, resulting in functional alterations. High affinity antibodies were detected in BC patients against 4-OHE2-HSA. Consequently, 4-OHE2-HSA may serve as a novel molecular target for potential cancer therapeutics. Furthermore, autoantibodies against 4-OHE2-HSA could serve as a potential biomarker for early detection of BC.

Assessment of IL-38 And IL-40 Levels in Gingival Crevicular Fluid in Gingivitis and Stage III Grade C Periodontitis: A Comparative Clinical Study

Periodontal diseases are infections of the supporting apparatus of teeth caused by microbial agents, and cytokines have an important role in the inflammatory response. The purpose of this study is to measure the concentrations of interleukin-38 (IL-38) and interleukin-40 (IL-40) in the gingival crevicular fluid (GCF) in patients with stage III grade C periodontitis (SIII-GC), gingivitis and those with healthy periodontium. The study included a total of 75 people, 26 PH patients, 26 G patients, and 23 SIII-GC chronic periodontitis patients. Clinical parameters of a patient such as plaque index (PI), gingival index (GI), bleeding upon probing (BOP), probing pocket depth (PPD) and clinical attachment loss (CAL) were analyzed. GCF was collected and measured using the ELISA technique with IL-38 and IL-40 specific antibodies and kits. Interleukin-38 and interleukin-40 of the SIII-GC periodontitis group was significantly higher (P &lt; 0.05) than other groups as regards normal gingival crevicular fluid IL-38 and IL-40 levels. However, differences in IL-38 and IL-40 levels were not significant between the two other groups: PH and G ones (P &gt; 0.05). Positive correlation was found between GCF derived IL-38 and IL-40 levels with clinical periodontal parameters from sampled areas (P &lt; 0.001). The strongest findings of this research indicate that within GCF, both IL-38 and IL-40 levels were elevated as total GCF IL-38 and total GCF IL-40 levels in different patients were high.

Recombinant IL-34 alleviates bacterial enteritis in Megalobrama amblycephala by strengthening the intestinal barrier

The potential role of interleukin-34 (IL-34), an important cytokine that regulates intestinal function in mammals, is currently being explored in the context of fish intestinal diseases. In this study, we assessed the preventive potential of recombinant Megalobrama amblycephala IL-34 (rMaIL-34) protein in bacterial enteritis. MaIL-34 exhibited conserved structural and evolutionary features with teleost IL-34 and was found to be involved in the intestinal immune response to Aeromonas hydrophila infection. Furthermore, treatment with rMaIL-34 significantly improved the survival rate of M. amblycephala following A. hydrophila infection and alleviated the symptoms of enteritis in these fish. In vivo, rMaIL-34 enhanced goblet cell proliferation and mucus layer tightness, thereby maintaining mucosal integrity following infection. Additionally, rMaIL-34 attenuated the decrease in ZO-1 expression and inhibited the increase in intestinal permeability caused by A. hydrophila, thereby reducing the concentrations of DAO and D-LAC in the plasma. Furthermore, rMaIL-34 suppressed oxidative stress, apoptosis, and inflammatory responses triggered by A. hydrophila, thereby strengthening the immune barrier. At the microbiological level, rMaIL-34 contributed to improved intestinal microbiota distribution and enhanced the functions of intestinal microbiota in terms of energy metabolism, antibiotic biosynthesis, and oxidative phosphorylation. This study reveals, for the first time, the multiple roles of fish IL-34 in resistance to bacterial enteritis and paves the way for the development of rMaIL-34 as an immunotherapy for bacterial enteritis in fish.

Mathematical model of tumor immune microenvironment with application to the combined therapy targeting the PD-1/PD-L1 pathway and IL-10 cytokine antibody.

The tumor microenvironment constitutes a complex system shaped by the intricate interactions among tumor cells, immune cells, and cytokines. Within this environment, the interplay between immune cells and cytokines is crucial in influencing tumor growth and progression. Despite advancements in clinical tumor immunotherapy, there remains a gap in comprehensive simulations of tumor immune responses, particularly regarding cytokine-driven processes. This study aims toaddress this gap by investigating the regulatory interactions among tumor cells, immune cells, and cytokines to simulate the complexities of tumor immunotherapy. We develop a comprehensive modeling and computational framework incorporating PD-1 inhibitors and interleukin-10 (IL-10) antibodies. Through detailed mathematical analysis, we elucidate the impact of changes in the immune microenvironment on tumor cellsnumber. Our findings highlight the significant therapeutic effect of anti-PD-1 and IL-10 inhibitors, with increased drug dosage correlating with a reduction in tumor burden. Furthermore, combination therapy demonstrates a marked extension of survival with reduced dosages compared to monotherapy. Based on model simulations, we proposed prognostic predictions by assessing the microenvironmental status before treatment. The findings indicate a promising method forenhancing treatment effectiveness and offering potentialadvantages to patients receiving tumor immunotherapy.

Nicotinamide mononucleotide improves the ovarian reserve of POI by inhibiting NLRP3-mediated pyroptosis of ovarian granulosa cells

BackgroundPremature ovarian insufficiency (POI) is a common clinical problem, but there is currently no effective treatment. NLRP3 inflammasome-induced pyroptosis is thought to be a possible mechanism of POI. Nicotinamide mononucleotide (NMN) has a certain anti-inflammatory effect, providing a promising approach for the treatment of POI.MethodsThirty female Sprague Dawley rats were randomly divided into a control group (n = 10) and a POI group (n = 20). Cyclophosphamide (CTX) was administered for 2 weeks to induce POI. Then the POI group was divided into two groups: the CTX-POI group (n = 10), which was given saline; and the CTX-POI + NMN group (n = 10), which was given NMN at a dose of 500 mg/kg/day for 21 consecutive days. At the end of the study, the serum hormone concentrations of each group were determined, and each group was subjected to biochemical, histopathological, and immunohistochemical analyses. In the in vitro experiment, cell pyroptosis was simulated by using lipopolysaccharide (LPS) and nigricin (Nig), and then KGN cells were treated with NMN, MCC950, and AGK2, and the levels of Nicotinamide adenine dinucleotide (NAD+) and inflammatory factors Interleukin-18(IL-18) and Interleukin-1β(IL-1β) in the cell supernatants were detected, and the levels of pyroptosis-related factors in the cells were determined.ResultsIn POI rats, NMN treatments can improve blood hormone levels and partially improve the number of follicles, enhance ovarian reserve function and ovarian index.The evidence is that the increase in NAD+ levels and the activation of SIRT2 expression can reduce the expression of NLRP3, Gasdermin D (GSDMD), Caspase-1, IL-18, and IL-1β in the ovary.ConclusionNMN improves CTX-induced POI by inhibiting NLRP3-mediated pyroptosis, providing a new therapeutic strategy and drug target for clinical POI patients.

Effect of the Zushima patch combined with celecoxib on pain and inflammatory factor expression in knee osteoarthritis with cold‐dampness obstruction

AbstractBackgroundKnee osteoarthritis (KOA) is a chronic degenerative joint disease that frequently occurs in middle‐aged and older individuals. Although celecoxib is a commonly used drug for the treatment of KOA, its efficacy and safety have limitations. Zushima, a traditional Chinese medicine, is commonly used for treating joint pain and has anti‐inflammatory and analgesic properties. This study aims to explore the effect of the Zushima patch combined with celecoxib on pain and inflammatory factor expression in knee osteoarthritis (KOA) patients with cold‐dampness obstruction.MethodsA total of 100 patients with KOA of cold‐dampness obstruction were randomly divided into a treatment group (n = 50) and a control group (n = 50). Patients in the control group received oral administration of celecoxib capsules, whereas the treatment group received the Zushima patch combined with oral administration of celecoxib capsules. Then, the efficacy and safety were compared, together with the traditional Chinese medicine (TCM) syndrome score, pain, and knee joint function. We also determined the concentrations of osteoprotegerin (OPG), insulin‐like growth factor (IGF‐1), osteocalcin (OC), and inflammatory factors such as interleukin‐1β (IL‐1β), interleukin‐6 (IL‐6), and C‐reactive protein (CRP). Finally, the safety between the two groups was compared.ResultsThe total effective rate in the treatment group was significantly higher than that in the control group. After treatment, the levels of the TCM syndrome score, pain score, IL‐1, IL‐6, and CRP in the treatment group showed significant decreases compared with those in the control group, while the scores of OPG, IGF‐1, OC, and knee joint function in the treatment group showed significant increases compared with those in the control group. There was no significant difference in adverse events between the two groups.ConclusionsThe Zushima patch combined with celecoxib could relieve the pain of KOA with cold‐dampness obstruction and improve knee joint function. These effects may be the result of the downregulation of inflammatory factors and the regulation of joint fluid‐related indices.

Temperature-Responsive Hydrogel System Integrating Wound Temperature Monitoring and On-demand Drug Release for Sequentially Inflammatory Process Regulation of Wound Healing.

Wound healing faces challenges like inflammation, infection, and limited monitoring capabilities, and traditional dressings often lack the ability to promote healing or provide real-time wound status updates. Early pro-inflammatory responses help clear pathogens and damaged tissue, while timely anti-inflammatory modulation aids tissue regeneration, making sequential inflammation regulation crucial. Additionally, wound temperature, a key infection biomarker, enables real-time monitoring for effective management. We propose a temperature-responsive hydrogel dressing capable of two-stage sequential drug release and wound temperature monitoring. The hydrogel, composed of poly(N-isopropylacrylamide) (PNIPAM) and dopamine/methacrylated-modified hyaluronic acid (HA-MA-DA), allows temperature-based drug release control, sequential regulating pro-inflammatory and anti-inflammatory stages in wound healing. Interleukin-8 (IL-8), a pro-inflammatory molecule, is encapsulated into hydrogel matrix and rapidly released to trigger the initial inflammatory response. Furthermore, photothermally responsive and erastin-loaded polydopamine@PNIPAM nanoparticles (E-PD NPs) are incorporated to release the anti-inflammatory drug erastin upon near-infrared light exposure, terminating inflammation through cytosolic burial, and thus achieve anti-inflammatory effects at the second stage of wound healing. Furthermore, a bluetooth module enables real-time wound temperature monitoring. Combining sequential drug release with temperature monitoring, our hydrogel dressing addresses significant gaps in current wound healing technologies and offers new insights into personalized therapeutic interventions.

IL7 as a Risk Factor for Prostate Cancer: Implications for T Cell Apoptosis and Infiltration in the Tumor Microenvironment.

Prostate cancer's complex interplay with the immune microenvironment prompted an investigation into immune-related pathogenic mechanisms and potential therapeutic targets. Within the GSE176031 data set, Seurat meticulously dissected single-cell profiles from radical prostatectomy patients. Leveraging CellMarker and SingleR cell identities were precisely annotated. Then, monocle traced pseudotime trajectories, illuminating cellular paths, complemented by CellChat's insights into intricate intercellular communications. Furthermore, mendelian randomization (MR) robustly substantiated causal associations within prostate cancer contexts. Employing single-cell analysis on intraoperative tumor and normal tissue, we identified 15 distinct cell types, notably observing a significant T cell reduction in tumor samples. Intercellular communication analysis revealed multiple pathways between epithelial cells and T cells, highlighting interleukin (IL)-IL7R-IL2RG interactions. IL7R, crucial in T cell apoptosis, showed differential expression across T cell development stages. Patients with IL7 amplification had poorer outcomes (p < 0.05), supported by MR in two cohorts (ieu-b-4809 cohort: odds ratio [OR] = 1.005, p = 0.002, 95% confidence interval [CI] [1.002-1.008]; ebi-a-GCST90018905: OR = 1.063, p = 0.032, 95% CI [1.005-1.125]), confirming IL7 as a prostate cancer risk factor. These findings suggest T cell depletion via IL7-IL7R signaling may drive prostate cancer progression, offering novel therapeutic insights.

Efficacy of serum-free cultured human umbilical cord mesenchymal stem cells in the treatment of knee osteoarthritis in mice.

We investigated the efficacy of intra-articular injection of human umbilical cord mesenchymal stem cells (hUC-MSCs) for the treatment of osteoarthritis (OA) progression in the knee joint. Although many experimental studies of hUC-MSCs have been published, these studies have mainly used fetal bovine serum-containing cultures of hUC-MSCs; serum-free cultures generally avoid the shortcomings of serum-containing cultures and are not subject to ethical limitations, have a wide range of prospects for clinical application, and provide a basis or animal experimentation for clinical experiments. To study the therapeutic effects of serum-free hUC-MSCs (N-hUCMSCs) in a mouse model of knee OA. Fifty-five male C57BL/6 mice were randomly divided into six groups: The blank control group, model control group, serum-containing hUC-MSCs (S-hUCMSC) group, N-hUCMSC group and hyaluronic acid (HA) group. After 9 weeks of modeling, the serum levels of interleukin (IL)-1β and IL-1 were determined. Hematoxylin-eosin staining was used to observe the cartilage tissue, and the Mankin score was determined. Immunohistochemistry and western blotting were used to determine the expression of collagen type II, matrix metalloproteinase (MMP)-1 and MMP-13. The Mankin score and serum IL-1 and IL-1β and cartilage tissue MMP-1 and MMP-13 expression were significantly greater in the experimental group than in the blank control group (P < 0.05). Collagen II expression in the experimental group was significantly lower than that in the blank control group (P < 0.05). The Mankin score and serum IL-1 and IL-1β and cartilage tissue MMP-1 and MMP-13 levels the experimental group were lower than those in the model control group (P < 0.05). Collagen II expression in the experimental group was significantly greater than that in the model control group (P < 0.05). N-hUCMSC treatment significantly alleviate the pathological damage caused by OA. The treatment effects of the S- hUCMSC group and HA group were similar.