Interplay Of Cytokines Research Articles

Unraveling the bidirectional relationship between muscle inflammation and satellite cells activity: influencing factors and insights.

Inflammation stands as a vital and innate function of the immune system, essential for maintaining physiological homeostasis. Its role in skeletal muscle regeneration is pivotal, with the activation of satellite cells (SCs) driving the repair and generation of new myofibers. However, the relationship between inflammation and SCs is intricate, influenced by various factors. Muscle injury and repair prompt significant infiltration of immune cells, particularly macrophages, into the muscle tissue. The interplay of cytokines and chemokines from diverse cell types, including immune cells, fibroadipogenic progenitors, and SCs, further shapes the inflammation-SCs dynamic. While some studies suggest heightened inflammation associates with reduced SC activity and increased fibro- or adipogenesis, others indicate an inflammatory stimulus benefits SC function. Yet, the existing literature struggles to delineate clearly between the stimulatory and inhibitory effects of inflammation on SCs and muscle regeneration. This paper comprehensively reviews studies exploring the impact of pharmacological agents, dietary interventions, genetic factors, and exercise regimes on the interplay between inflammation and SC activity.

Bioengineered Silk Fibroin Hydrogel Reinforced with Collagen-Like Protein Chimeras for Improved Wound Healing.

The study investigates the potentials of the rapid crosslinking hydrogel concoction comprising of natural silk fibroin (SF) and recombinant tailorable collagen-like protein with binding domains for wound repair. The formation of dityrosine crosslinks between the tyrosine moieties augments the formation of stable hydrogels, in the presence of the cytocompatible photo-initiator riboflavin and visible light. This uniquely engineered PASCH (Photo-activated silk fibroin and tailor-made collagen-like protein hydrogel) confers the key advantage of improved biological properties over the control hydrogels comprising only of SF. The physico-chemical characterization of the hydrogels with respect to crosslinking, modulus, and thermal stability delineates the ascendancy of PASCH 7:3 over other combinations. Furthermore, the hybrid protein hydrogel proves to be a favorable cellular matrix as it enhances cell adhesion, elongation, growth, and proliferation in vitro. Time-lapse microscopy studies reveal an enhanced wound closure in human endothelial cell monolayer (EA.hy926), while the gene expression studies portray the dynamic interplay of cytokines and growth factors in the wound milieu facilitating the repair and regeneration of cells, sculpted by the proteins. The results demonstrate the improved physical and biological properties of fabricated PASCH, depicting their synergism, and implying their competency for use in tissue engineering applications.

Cytokine profiles and their correlation with clinical and blood parameters in rheumatoid arthritis and systemic lupus erythematosus.

The abnormal biological activity of cytokines and their imbalance are implicated in developing rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Cytokine levels were measured in RA and SLE patients and compared to healthy controls using the Wilcoxon rank sum test and Kruskal-Wallis test. The relationship between cytokine levels and blood and clinical parameters was assessed using Spearman's correlation test. Compared to healthy controls, both RA and SLE patients exhibited elevated levels of GM-CSF, CX3CL1, IFN-α2, IL-12p70, IL-17A, TNF-α, IL-1β, and IFN-γ, which is evidence of their shared inflammatory signature. IL-2 levels were elevated exclusively in RA patients, while MCP-1 and IL-10 were uniquely increased in SLE patients. Notably, TNF-α showed the most significant increase in SLE patients. IL-4 was elevated in SLE patients with nephritis, correlating with IL-6, IL-10, sCD40L, and IL-8, suggesting B cell involvement in lupus nephritis. The negative correlation between CX3CL1 and TNF-α with HDL in RA and SLE respectively, highlights the potential association of these inflammatory markers with cardiovascular risk. These findings underscore the complex cytokine interplay in RA and SLE. CX3CL1 emerges as a potential therapeutic target for RA, while TNF-α and IL-4 show promise as therapeutic targets for SLE.

The roles of genetic mutation and cytokines/chemokines in immune response and their association with uveal melanoma patient outcome

The impact of tumor mutations and the interplay of cytokines and chemokines on the immune response and clinical outcomes in uveal melanoma (UM) warrants further exploration. In our study, we delved into the correlation between genetic alterations and survival rates in a cohort of 188 UM patients, utilizing data from cBioPortal. We assessed the composition of immune cell populations within 80 UM tumors by examining RNA sequence-based gene expression data from The Cancer Genome Atlas (TCGA). Furthermore, we scrutinized the relationship between genetic mutations and the expression of cytokines and chemokines, as well as their influence on various immune cell subsets. Our investigation revealed a significant association between the presence of mutated GNAQ or SF3B1 genes and improved progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS) when compared to patients with non-mutated counterparts. In contrast, the presence of immune response gene mutations was associated with a detrimental effect on PFS, DSS, and OS. We also observed that the expression levels of cytokines and chemokines were positively linked to the infiltration of immune killer cells and inversely related to the populations of B cells and dendritic cells. Elevated expression levels of PDCD1, TNF, IL6, CXCL9, and CXCL10 were found to be correlated with reduced OS. Intriguingly, an increase in CD8+ T cell populations was associated with a poorer OS, a finding that warrants further investigation. These findings underscore the potential utility of cytokines/chemokines expression levels, immune cell subsets, and mutation status as critical biomarkers for the selection of patients who are most likely to benefit from immunotherapeutic interventions. Our research provides valuable insights that could guide the development of more targeted and effective treatment strategies for UM patients.

Alterations and associations between lung microbiota and metabolite profiles in silica-induced lung injury

Silicosis, caused by silica exposure, is the most widespread and deadliest occupational disease. However, effective treatments are lacking. Therefore, it is crucial to elucidate the mechanisms and targets involved in the development of silicosis. We investigated the basic processes of silicosis development and onset at different exposure durations (2 or 4 weeks) using various techniques such as histopathology, immunohistochemistry, Enzyme linked immunosorbent assay(ELISA),16 S rRNA, and untargeted metabolomics.These results indicate that exposure to silica leads to progressive damage to lung tissue with significant deterioration observed over time. Time-dependent cytokines such as the IL-4, IL-13, and IL-6 are detected in lung lavage fluid, the model group consistently exhibited elevated levels of these cytokines, indicating a persistent and worsening inflammatory response in the lungs. Meanwhile, HE and Masson results show that 4-week exposure to silica causes more obvious lung injury and pulmonary fibrosis. Besides, the model group consistently exhibited a distinct lung bacterial population, known as the Lachnospiraceae_NK4A136_group, regardless of exposure duration. However, with increasing exposure duration, specific temporal changes were observed in lung bacterial populations, including Haliangium, Allobaculum, and Sandaracinus (at 4 weeks; p < 0.05). Furthermore, our study revealed a strong correlation between the mechanism of silica-induced lung injury and three factors: oxidative stress, impaired lipid metabolism, and imbalanced amino acid metabolism. We observed a close correlation between cytokine levels, changes in lung microbiota, and metabolic disturbances during various exposure periods. These findings propose that a possible mechanism of silica-induced lung injury involves the interplay of cytokines, lung microbiota, and metabolites.

Generalized Pustular Psoriasis and Systemic Organ Dysfunctions.

This review explores the intricate relationship between generalized pustular psoriasis (GPP) and various systemic diseases, shedding light on the broader impacts of this severe skin condition beyond its primary dermatological manifestations. GPP is identified as not only a profound contributor to skin pathology but also a significant risk factor for systemic diseases affecting cardiovascular, hepatic, renal, pulmonary, and skeletal systems, as well as associated with an increased incidence of anemia, depression, anxiety, and arthritis. The research highlights the complex interplay of cytokines, particularly IL-17 and IL-36, which are central to the pathophysiology of GPP and implicated in the exacerbation of systemic conditions. Key findings indicate a higher incidence of cardiovascular events in GPP patients compared to those with other severe forms of psoriasis, notably with a stronger correlation between myocardial infarction history and GPP development. Liver disturbances, frequently reversible upon psoriasis remission, suggest a cytokine-mediated link to hepatic health. Renal dysfunction appears elevated in GPP sufferers, with IL-17 and IL-36 potentially driving renal fibrosis. Similarly, interstitial lung disease and osteoporosis in GPP patients underscore the systemic reach of inflammatory processes initiated in the skin. The associations with anemia, depression, anxiety, and arthritis further complicate the clinical management of GPP, requiring a multidisciplinary approach. The study concludes that managing GPP effectively requires a holistic approach that addresses both the cutaneous and systemic dimensions of the disease, advocating for continued research into the mechanisms that connect GPP with broader health implications to refine therapeutic strategies.

Interplay of Cytokines and Chemokines in Aspergillosis.

Aspergillosis is a fungal infection caused by various species of Aspergillus, most notably A. fumigatus. This fungus causes a spectrum of diseases, including allergic bronchopulmonary aspergillosis, aspergilloma, chronic pulmonary aspergillosis, and invasive aspergillosis. The clinical manifestations and severity of aspergillosis can vary depending on individual immune status and the specific species of Aspergillus involved. The recognition of Aspergillus involves pathogen-associated molecular patterns (PAMPs) such as glucan, galactomannan, mannose, and conidial surface proteins. These are recognized by the pathogen recognition receptors present on immune cells such as Toll-like receptors (TLR-1,2,3,4, etc.) and C-type lectins (Dectin-1 and Dectin-2). We discuss the roles of cytokines and pathogen recognition in aspergillosis from both the perspective of human and experimental infection. Several cytokines and chemokines have been implicated in the immune response to Aspergillus infection, including interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), CCR4, CCR17, and other interleukins. For example, allergic bronchopulmonary aspergillosis (ABPA) is characterized by Th2 and Th9 cell-type immunity and involves interleukin (IL)-4, IL-5, IL-13, and IL-10. In contrast, it has been observed that invasive aspergillosis involves Th1 and Th17 cell-type immunity via IFN-γ, IL-1, IL-6, and IL-17. These cytokines activate various immune cells and stimulate the production of other immune molecules, such as antimicrobial peptides and reactive oxygen species, which aid in the clearance of the fungal pathogen. Moreover, they help to initiate and coordinate the immune response, recruit immune cells to the site of infection, and promote clearance of the fungus. Insight into the host response from both human and animal studies may aid in understanding the immune response in aspergillosis, possibly leading to harnessing the power of cytokines or cytokine (receptor) antagonists and transforming them into precise immunotherapeutic strategies. This could advance personalized medicine.

Interplay of cytokines in the pathophysiology of atopic dermatitis: insights from Murin models and human.

The pathogenesis of atopic dermatitis (AD) is understood to be crucially influenced by three main factors: dysregulation of the immune response, barrier dysfunction, and pruritus. In the lesional skin of AD, various innate immune cells, including Th2 cells, type 2 innate lymphoid cells (ILC2s), and basophils, produce Th2 cytokines [interleukin (IL)-4, IL-5, IL-13, IL-31]. Alarmins such as TSLP, IL-25, and IL-33 are also produced by epidermal keratinocytes, amplifying type 2 inflammation. In the chronic phase, not only Th2 cells but also Th22 and Th17 cells increase in number, leading to suppression of filaggrin expression by IL-4, IL-13, and IL-22, which further deteriorates the epidermal barrier function. Dupilumab, which targets IL-4 and IL-13, has shown efficacy in treating moderate to severe AD. Nemolizumab, targeting IL-31RA, effectively reduces pruritus in AD patients. In addition, clinical trials with fezakinumab, targeting IL-22, have demonstrated promising results, particularly in severe AD cases. Conversely, in murine models of AD, several cytokines, initially regarded as promising therapeutic targets, have not demonstrated sufficient efficacy in clinical trials. IL-33 has been identified as a potent activator of immune cells, exacerbating AD in murine models and correlating with disease severity in human patients. However, treatments targeting IL-33 have not shown sufficient efficacy in clinical trials. Similarly, thymic stromal lymphopoietin (TSLP), integral to type 2 immune responses, induces dermatitis in animal models and is elevated in human AD, yet clinical treatments like tezepelumab exhibit limited efficacy. Therapies targeting IL-1α, IL-5, and IL-17 also failed to achieve sufficient efficacy in clinical trials. It has become clear that for treating AD, IL-4, IL-13, and IL-31 are relevant therapeutic targets during the acute phase, while IL-22 emerges as a target in more severe cases. This delineation underscores the necessity of considering distinct pathophysiological aspects and therapeutic targets in AD between mouse models and humans. Consequently, this review delineates the distinct roles of cytokines in the pathogenesis of AD, juxtaposing their significance in human AD from clinical trials against insights gleaned from AD mouse models. This approach will improve our understanding of interspecies variation and facilitate a deeper insight into the pathogenesis of AD in humans.

Investigating Inflammatory Markers in Wound Healing: Understanding Implications and Identifying Artifacts.

Understanding the complex interplay of pro-inflammatory and anti-inflammatory cytokines is crucial in the field of wound healing, as it holds the key to developing effective therapeutics. In the initial stages of wound healing, pro-inflammatory cytokines like IL-1β, IL-6, TNF-α, and various chemokines play vital roles in recruiting cells for debris clearance and the recruitment of growth factors. Careful regulation and timely resolution of this early inflammation are essential for optimal wound repair. As the healing process progresses, anti-inflammatory proteins such as IL-10 and IL-4 become instrumental in facilitating the transition to later stages where pro-inflammatory cytokines promote angiogenesis and wound remodeling. This Perspective underscores the complexity of inflammatory cytokines in wound healing research and emphasizes the need for comprehensive and unbiased methodologies in their evaluation. For robust and reliable results in wound-healing research, a more holistic approach is necessary-one that considers the roles, interactions, and timing of biological molecules, alongside careful sampling and evaluation strategies.

Mathematical models disentangle the role of IL-10 feedbacks in human monocytes upon proinflammatory activation

Inflammation is one of the vital mechanisms through which the immune system responds to harmful stimuli. During inflammation, proinflammatory and anti-inflammatory cytokines interplay to orchestrate fine-tuned and dynamic immune responses. The cytokine interplay governs switches in the inflammatory response and dictates the propagation and development of the inflammatory response. Molecular pathways underlying the interplay are complex, and time-resolved monitoring of mediators and cytokines is necessary as a basis to study them in detail. Our understanding can be advanced by mathematical models that enable to analyze the system of interactions and their dynamical interplay in detail. We, therefore, used a mathematical modeling approach to study the interplay between prominent proinflammatory and anti-inflammatory cytokines with a focus on tumor necrosis factor and interleukin 10 (IL-10) in lipopolysaccharide-primed primary human monocytes. Relevant time-resolved data were generated by experimentally adding or blocking IL-10 at different time points. The model was successfully trained and could predict independent validation data and was further used to perform simulations to disentangle the role of IL-10 feedbacks during an acute inflammatory event. We used the insight to obtain a reduced predictive model including only the necessary IL-10-mediated feedbacks. Finally, the validated reduced model was used to predict early IL-10-tumor necrosis factor switches in the inflammatory response. Overall, we gained detailed insights into fine-tuning of inflammatory responses in human monocytes and present a model for further use in studying the complex and dynamic process of cytokine-regulated acute inflammation.

Sarcopenic Obesity in People with Alcoholic Use Disorder: Relation with Inflammation, Vascular Risk Factors and Serum Vitamin D Levels.

In recent years, the terms sarcopenia, sarcopenic obesity, and osteosarcopenic obesity (OSO) were coined to define a situation in elderly people strongly associated with frailty and increased mortality. Possibly, a complex interplay of several hormones and cytokines are involved in its development. Ongoing research detected that OSO may occur at any age and in several conditions. The prevalence of OSO in alcoholism was poorly analyzed. The aim of this study was to analyze the prevalence of OSO in alcoholism and its relationship with proinflammatory cytokines and/or common complications of alcoholism, such as cirrhosis, cancer, or vascular disease. We included 115 patients with alcoholic use disorder. Body composition analysis was performed by double X-ray absorptiometry. Handgrip strength was recorded using a dynamometer. We assessed liver function according to Child's classification, and determined serum levels of proinflammatory cytokines (TNF-α, IL-6, IL-8), routine laboratory variables, and vitamin D. People with alcoholic use disorder showed a high prevalence of OSO, especially regarding OSO obesity (60%), OSO osteopenia (55.65%), and OSO lean mass (60.17%). OSO handgrip was closely, independently, related to the presence of vascular calcification (χ2 = 17.00; p < 0.001). OSO handgrip was related to several proinflammatory cytokines and vitamin D. Vitamin D deficiency kept a close correlation with OSO handgrip (rho = -0.54, p < 0.001). Therefore, among people with alcohol use disorder, OSO prevalence was high. OSO handgrip is related to serum proinflammatory cytokine levels supporting the possible pathogenetic role of these cytokines on OSO development. Vitamin D deficiency is related to OSO handgrip suggesting its pathogenetic involvement in sarcopenia in patients with alcohol use disorder. The close association between OSO handgrip and vascular calcification is clinically relevant and suggests that OSO handgrip may constitute a prognostic tool in these patients.

The Tumor Immune Microenvironment in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a type of kidney cancer that arises from the cells lining the tubes of the kidney. The tumor immune microenvironment (TIME) of ccRCC is a complex interplay of various immune cells, cytokines, and signaling pathways. One of the critical features of the ccRCC TIME is the presence of infiltrating immune cells, including T cells, B cells, natural killer cells, dendritic cells, and myeloid-derived suppressor cells. Among these cells, CD8+ T cells are particularly important in controlling tumor growth by recognizing and killing cancer cells. However, the TIME of ccRCC is also characterized by an immunosuppressive environment that hinders the function of immune cells. Several mechanisms contribute to the immunosuppressive nature of the ccRCC TIME. For instance, ccRCC cells produce cytokines such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β), which suppress immune cell activation and promote the differentiation of regulatory T cells (Tregs). Tregs, in turn, dampen the activity of effector T cells and promote tumor growth. In addition, ccRCC cells can express programmed death-ligand 1 (PD-L1), which interacts with the programmed cell death protein 1 (PD-1) receptor on T cells to inhibit their function. In addition, other immune checkpoint proteins, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and lymphocyte activation gene 3 (LAG-3), also contribute to the immunosuppressive milieu of the ccRCC TIME. Finally, the hypoxic and nutrient-poor microenvironment of ccRCC can stimulate the production of immunosuppressive metabolites, such as adenosine and kynurenine, which further impair the function of immune cells. Understanding the complex interplay between tumor cells and the immune system in the ccRCC TIME is crucial for developing effective immunotherapies to treat this disease.

OBESITY AS A RISK FACTOR FOR DIFFERENT TYPES OF CANCER

Over the last few decades, the incidence of obesity is increasing which is now recognized as public health issue worldwide. Obesity has been associated with an elevated risk of several types of metabolic syndrome and malignancies. This article reviews the latest evidence on the association between higher Body Mass Index (BMI) and cancer, discovering the essential biological mechanism and pathways such as the interplay of adipokines, cytokines, and growth factors. Furthermore, it provides intuition into the effects of obesity on proliferation and metastasis. In last, it highlights the need for a comprehensive approach to tackle the obesity pandemic including changes in lifestyle and regular cancer to enhance the quality of life.

Regulation of cells of the arterial wall by hypoxia and its role in the development of atherosclerosis.

The cell's response to hypoxia depends on stabilization of the hypoxia-inducible factor 1 complex and transactivation of nuclear factor kappa-B (NF-κB). HIF target gene transcription in cells resident to atherosclerotic lesions adjoins a complex interplay of cytokines and mediators of inflammation affecting cholesterol uptake, migration, and inflammation. Maladaptive activation of the HIF-pathway and transactivation of nuclear factor kappa-B causes monocytes to invade early atherosclerotic lesions, maintaining inflammation and aggravating a low-oxygen environment. Meanwhile HIF-dependent upregulation of the ATP-binding cassette transporter ABCA1 causes attenuation of cholesterol efflux and ultimately macrophages becoming foam cells. Hypoxia facilitates neovascularization by upregulation of vascular endothelial growth factor (VEGF) secreted by endothelial cells and vascular smooth muscle cells lining the arterial wall destabilizing the plaque. HIF-knockout animal models and inhibitor studies were able to show beneficial effects on atherogenesis by counteracting the HIF-pathway in the cell wall. In this review the authors elaborate on the up-to-date literature on regulation of cells of the arterial wall through activation of HIF-1α and its effect on atherosclerotic plaque formation.

The Potential Prognostic, Diagnostic and Therapeutic Targets for Recurrent Arrhythmias in Patients with Coronary Restenosis and Reocclusions After Coronary Stenting.

The interplay of oxidative stress, proinflammatory microparticles, and proinflammatory cytokines in recurrent arrhythmias is unknown in elderly patients with coronary restenosis and reocclusions after coronary stenting. This research sought to investigate the potential diagnostic and therapeutic targets for recurrent arrhythmias in patients with coronary restenosis and reocclusions after coronary stenting. We examined whether oxidative stress, proinflammatory microparticles, and proinflammatory cytokines could have effects that lead to recurrent arrhythmias in elderly patients with coronary restenosis and reocclusions. We measured the levels of malondialdehyde (MDA), CD31 + endothelial microparticle (CD31 EMP), CD62E + endothelial microparticle (CD62E + EMP), high-sensitivity C-reactive protein (hs-CRP), interleukin- 1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α), as well as oxidized low-density lipoprotein (OX-LDL), and assessed the effects of relationship between oxidative stress, proinflammatory microparticles, and proinflammatory cytokines on recurrent atrial and ventricular arrhythmias in elderly patients with coronary restenosis and reocclusions after coronary stenting. The levels of CD31 + EMP, CD62E + EMP, MDA, hs-CRP, IL-1β, IL-6, IL-8, TNF-α and OX-LDL were found to be increased significantly in coronary restenosis + recurrent atrial arrhythmia group compared to without coronary restenosis and coronary restenosis + without recurrent atrial arrhythmia groups, respectively (P < 0.001). Patients in the coronary reocclusion + recurrent ventricular arrhythmia group also exhibited significantly increased levels of CD31 + EMP, CD62E + EMP, MDA, hs-CRP, IL-1β, IL-6, IL-8, TNF-α and OXLDL compared to without coronary reocclusion and coronary reocclusion + without recurrent ventricular arrhythmia groups, respectively (P < 0.001). Proinflammatory microparticles, proinflammatory cytokines, and oxidative stress might act as potential targets for recurrent arrhythmias in patients with coronary restenosis and reocclusions after coronary stenting.

Changes of th1 and th2 cytokines levels among sudanese tuberculosis patients during treatment.

The interaction of T cells with infected macrophages depends on the interplay of cytokines produced in each cell, and this mechanism is a key to protective immunity against Mycobacterium tuberculosis. Extensive research has been devoted to studying the changes in systemic cytokine levels in patients with tuberculosis (TB), but the results are inconclusive. Determine Th1 and Th2 cytokine immune response levels among new TB patients compared to follow-up and healthy control. Cross-sectional laboratory-based study. Immunology Laboratory, National Center for Research. Blood samples (n = 145) were collected from confirmed new TB cases, follow-up TB cases, and from healthy controls. Participants were initially diagnosed by microcopy using Ziehl-Neelsen smear method and confirmed by polymerase chain reaction using IS6110. Cytokine levels (interleukin-10 [IL-10], tumor necrosis factor alpha [TNF-α], and Interferon-gamma [IFN-γ]) were measured directly from plasma using sandwich enzyme-linked immunosorbent assay. Measuring Th1 cytokines (IFN-γ and TNF-α) and Th2 cytokine (IL-10). One hundred and forty-five cases (new TB cases, 85; follow-up, 25; and healthy control, 35) were included in this study. The study population were mainly males (70.3%) compared to females (29.7%) and 87.5% aged between 21 to 60 year. The plasma IFN-γ levels were found significantly higher in new TB cases (mean 35.38 pg/m; confidence interval: 29.32-41.43) than in the follow-up patients and the healthy control (P = 0.000). There were no significant differences in TNF-α and IL-10 levels among the new TB cases and the follow-up and healthy control (P = 0.852 and P = 0.340, respectively). Direct plasma IFN-γ level can be used in TB patient follow-up as a recovery marker as it correlated well with the appearance of the disease and treatment response.

Resolution of Th/Tc17-driven inflammation during anti-TNFα treatment of rheumatoid arthritis reveals a unique immune biomarker profiling pattern.

Rheumatoid arthritis (RA) is a chronic multisystem disease with a complex immunopathology. Its inflammatory state is dominated by pro-inflammatory cytokines such as TNFα and activated Th1/Th17. Only proportion of patients achieve clinical remission despite potent biologics targeting these pathways. This study investigated the resolution of inflammation in RA patients (naïve for biologics) receiving TNFα inhibitors (TNFi) and evaluated the biological mechanisms behind treatment response and assessed them using clinical scoring systems. The majority showed a good clinical response after six months (6M) and a significant drop in DAS28-CRP (P≤.002), CDAI (P≤.0001) and RheumXpert (P≤.0001). Before treatment, the patients demonstrated a chronic innate and adaptive inflammatory state. The improved clinical condition was reflected with a decrease in Th17/Tc17 (P≤.05) and an increase in Tregs after 6M (P≤.05). Using a logistic regression model on serum data, IL-6, IL-18, IL-21, IL-22, IFNγ and TNFα were identified as the main contributing biomarkers in the chronic inflammatory state of RA. A specific test score (STS) was defined and converted to a single cytokine composite test score (CCTS), which showed the disease outcome on a scale 0-100, providing sensitivity and specificity of ≥90%. Thus, the immunological complexity in RA is driven by a complex interplay of pro-inflammatory cytokines and effector T-cell response dominated by Th17/Tc17. In addition, the resolution of inflammation could be linked to a partially Treg-driven homeostatic innate immune response. Therefore, a more complex therapeutic approach against the above markers might be of value to obtain full clinical remission in the future.

Sinigrin in combination with artesunate provides protection against lethal murine malaria via falcipain-3 inhibition and immune modulation

Plant-derived antimalarials are indispensable for malaria treatment and a platform for new drugs. The present study explores sinigrin, for malaria using in vitro, in silico and in vivo strategies and the immune response generated after administration. The compound exhibited promising activity against chloroquine (CQ)-resistant (RKL-9) IC50 5.14 μg/mL and CQ-sensitive (3D7) IC50 5.47 μg/mL strains of P. falciparum and was safe in both in vitro (CC50 > 640 μg/mL) and in vivo (LD50 > 2 g/kg) toxicity studies. In addition, virtual screening showed hydrogen bonding, hydrophobic and van der Waals interactions with amino acid residues of 3BPM (falcipain-3). In vivo studies revealed promising antimalarial activity of sinigrin (200 mg/kg) with 87.44% chemo-suppression on day 5 and significantly (p < 0.0001) enhanced the mean survival time (21 ± 4.74 days) in contrast to the infected control (5.4 ± 1.14 days). In combination therapy, sinigrin (100 mg/kg and 200 mg/kg) augmented the efficacy of artesunate (AS 50 mg/kg) with 100% survival and no recrudescence. These observations are further corresponded and supported by DLC, NO production, cytokine analysis, biochemical and histopathological studies. Treatment with the combination resulted in a regulated interplay of immune cells and cytokines aiding in parasite clearance in addition to its specific inhibitory activity. We report the antimalarial activity of sinigrin first time with best D-score against falcipain-3. These findings highlight sinigrin as a HIT molecule, which may potentially be used in drug and vaccine development approaches.

CircSTK40 contributes to recurrent implantation failure via modulating the HSP90/AKT/FOXO1 axis

Increasing evidence has revealed a close relationship between non-coding RNAs and recurrent implantation failure (RIF). However, the role of circular RNAs (circRNAs) in RIF pathogenesis remains largely unknown. Microarray analyses were used to identify the differentially expressed circRNA-circSTK40. Functional experiments, including decidualization induction and terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay, were performed to determine the effects of circSTK40 on human endometrial stromal cells (ESCs). The interactions between circSTK40 and proteins were investigated by RNA pull-down, RNA immunoprecipitation, and co-immunoprecipitation (coIP) assays. We observed that circSTK40 expression was upregulated in the RIF midluteal-phase endometrial samples. circSTK40 overexpression in ESCs inhibited the decidualization process but concurrently enhanced cell survival during stress. Mechanistically, circSTK40 directly bound to HSP90 and CLU, thus functioning as a scaffold to block their interactions and hinder the proteasomal degradation of HSP90. The resulting high levels of HSP90 led to the activation of the AKT pathway and downregulation of FOXO1 expression. Inhibitors of AKT (MK-2206) and HSP90 (17AAG) both abolished the effects of circSTK40 overexpression in ESCs and increased the decidualization levels in a dose-dependent manner. Our findings indicate a novel epigenetic mechanism for RIF pathogenesis involving circSTK40 activity and provide a foundation for targeted treatments in patients with low endometrial receptivity.

Medical therapies for intra-hepatic cholangiocarcinoma

Medical therapies for intra-hepatic cholangiocarcinoma