Inhibition Of Cytokines Research Articles

Bryostatin-1 enhances the proliferation and functionality of exhausted CD8+ T cells by upregulating MAP Kinase 11

IntroductionBryostatin-1, a potent agonist of the protein kinase C, has been studied for HIV and cancer therapies. In HIV research, it has shown anti-HIV effects during acute infection and reactivation of latent HIV in chronic infection. As effective CD8+ T cell responses are essential for eliminating reactivated virus and achieving a cure, it is important to investigate how bryostatin-1 affects HIV-specific CD8+ T cells. HIV-specific CD8+ T cells often become exhausted, showing reduced proliferative potential and impaired cytokine production, a dysfunction also observed in cancer. Therefore, we further investigated how bryostatin-1 directly impacts exhausted CD8+ T cells.MethodsPBMCs from people with HIV (PWH) were treated with bryostatin-1 and tracked with proliferation dye for cell expansion. One day 6, HIV-specific CD8+ T cells were detected by tetramers staining and examined by flow cytometry. By utilizing an established in vitro murine T cell exhaustion system, changes in inhibitory receptors, transcription factors, cytokine production and killing capacity of bryostatin-1 treated exhausted CD8+ T cells were determined by flow cytometry. RNA-seq analysis was performed to study transcriptional changes in these cells.ResultsWe found that bryostatin-1 improved the expansion and decreased PD-1 expression of HIV-specific CD8+ T cells. Bryostatin-1 enhanced the functionality and proliferation while decreasing inhibitory receptor expression of in vitro generated exhausted CD8+ T cells. Bryostatin-1 upregulated TCF-1 and decreased TOX expression. These changes were confirmed through RNA-seq analysis. RNA-seq revealed that mitogen-activated protein kinases (MAPK) 11 was significantly downregulated in exhausted CD8+ T cells, however, it greatly upregulated after bryostatin-1 treatment. Inhibition of MAPK11 in bryostatin-1-treated cells blocked the increased proliferation and IFN-γ production induced by bryostatin-1, but did not affect other bryostatin-1 induced effects, such as the reduction of inhibitory receptors.DiscussionOur data demonstrate that bryostatin-1 induces a MAPK 11-dependent improvement in the proliferative and functional capacity of exhausted T cells. This study provides a rationale for bryostatin-1's potential to help eradicate the HIV reservoir during treatment, and it may also contribute to cancer immunotherapy by functionally improving exhausted CD8+ T cells.

Flexible and Robust Piezoelectric Chitosan Films with Enhanced Bioactivity.

Chitosan (CHT) is a known piezoelectric biomacromolecule; however, its usage is limited due to rapid degradation in an aqueous system. Herein, we prepared CHT film via a solvent casting method and cross-linked in an alkaline solution. Sodium hydroxide facilitated deprotonation, leading to increased intramolecular hydrogen bonding and mechanical properties. The CHT film remained intact for 30 days in aqueous environments. A systematic study revealed a gradual increase in the output voltage from 0.9 to 1.8 V under external force (1-16 N). In addition, the CHT film showed remarkable antibacterial and anti-inflammatory activities under ultrasound stimulation and inhibition of inflammatory cytokines. The CHT films also displayed enhanced cellular proliferation and ∼5-fold faster migration of NIH3T3 cells under US stimulation. Overall, this work presents a robust, biocompatible, and wearable CHT device that can transform biomechanical energy into electrical pulses for the modulation of cell fate processes and other bioactivities.

Mechanisms Underlying Vascular Inflammaging: Current Insights and Potential Treatment Approaches.

Inflammaging refers to chronic, low-grade inflammation that becomes more common with age and plays a central role in the pathophysiology of various vascular diseases. Key inflammatory mediators involved in inflammaging contribute to endothelial dysfunction and accelerate the progression of atherosclerosis. In addition, specific pathological mechanisms and the role of inflammasomes have emerged as critical drivers of immune responses within the vasculature. A comprehensive understanding of these processes may lead to innovative treatment strategies that could significantly improve the management of age-related vascular diseases. Emerging therapeutic approaches, including cytokine inhibitors, senolytics, and specialized pro-resolving mediators, aim to counteract inflammaging and restore vascular health. This review seeks to provide an in-depth exploration of the molecular pathways underlying vascular inflammaging and highlight potential therapeutic interventions.

Incidence of HBV Reactivation in Psoriasis Patients Undergoing Cytokine Inhibitor Therapy: A Single-Center Study and Systematic Review with a Meta-Analysis

Background: Psoriasis patients who are seropositive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) face an elevated risk of hepatitis B virus reactivation (HBVr) when treated with cytokine inhibitors. This study aims to elucidate the risk in this population. Methods: A retrospective chart review was conducted to assess the risk of HBVr in 73 psoriasis patients treated with cytokine inhibitors from 2013 to 2023. Additionally, a systematic review and meta-analysis were performed, pooling data from 10 studies (including our cohort) and adhering to PRISMA guidelines. Statistical heterogeneity was assessed using the I2 statistic, and pooled proportions were calculated using a random effects model. Results: No HBVr cases were observed among the 11 HBsAg+ patients in the cohort. However, two of the sixty-two (3.2%) HBsAg−/HBcAb+ patients experienced reactivation during therapy, with outcomes ranging from spontaneous recovery in one case to death from hepatic failure despite antiviral treatment in the other. The meta-analysis, pooling data from 10 studies, revealed a reactivation rate of 21.2% (95% CI: 9.4–41.0%) in HBsAg+ patients without prophylaxis and 4.4% (95% CI: 2.2–8.7%) in HBsAg−/HBcAb+ patients. Conclusion: Antiviral prophylaxis is essential for HBsAg+ patients receiving cytokine inhibitors, given the high risk of reactivation. Despite the lower risk for HBsAg−/HBcAb+ patients, the potential severity of outcomes demands careful monitoring and timely action.

Beneficial effects of ultrafine bubble shower on a mouse model of atopic dermatitis.

Atopic dermatitis (AD) is a common and relapsing skin disease characterized by skin barrier dysfunction, inflammation, and chronic pruritus. Both cutaneous barrier dysfunction and immune dysregulation are critical etiologies of the pathology of AD. Although various anti-inflammatory pharmacological agents, including cytokine inhibitors and signaling pathway blockers, have been developed recently, keeping the skin clean is of utmost importance in maintaining physiological cutaneous barrier function and avoiding an AD flare. Ultrafine bubbles (UFBs) are less than 1 μm in diameter and usually used to clean medical equipment. A UFB shower is expected to keep skin clean with attention to the temperature and strength of the shower. We examined the effects of a UFB shower on two mouse models of AD: Dermatophagoides farinae body (Dfb)- induced AD in NC/Nga mice and interleukin (IL)-33 transgenic (tg) mice. Each model comprised three groups: UFB shower-treated, normal shower-treated, and untreated. We evaluated the mice using a dermatitis score, scratching counts, histology, and the expression of inflammatory cytokines and skin barrier-related proteins. In the Dfb-induced AD mouse model, clinical features improved markedly in the UFB shower-treated mice compared to other groups. IL-4 and IL-13 levels decreased in the skin of normal and UFB shower-treated mice. In addition, in the skin of UFB shower-treated mice, the expression levels of skin barrier-related proteins were increased compared to normal showertreated mice. However, we found no significant differences in IL33tg mice. These results suggest that UFB shower can recover the skin barrier function and improve skin inflammation, especially in conditions such as extrinsic AD.

Investigation of Novel Aronia Bioactive Fraction-Alginic Acid Nanocomplex on the Enhanced Modulation of Neuroinflammation and Inhibition of Aβ Aggregation

Background/Objectives: Aronia extract or its active compounds, especially anthocyanin, have shown potential for Alzheimer’s disease (AD)-related pathologies, including neuroinflammation, fibrillogenesis of amyloid beta (Aβ), and cognitive impairment. However, there was still concern about their structural instability in vivo and in vitro. To solve the instability of anthocyanins, we combined aronia bioactive factions (ABFs) and alginic acid via electrostatic molecular interactions and created an ABF–alginic acid nanocomplex (AANCP). We evaluated whether it is more stable and effective in cognitive disorder mice and neuroinflammation cell models. Methods: The physicochemical properties of the AANCP, such as nanoparticle size, structural stability, and release rate, were characterized. The AANCP was administered to scopolamine-injected Balb/c mice, and to BV2 microglia treated with lipopolysaccharide (LPS) and amyloid beta (Aβ). Inflammation responses were measured via qPCR and ELISA in vitro, and cognitive functions were measured via behavior tests in vivo. Results: The AANCP readily formed nanoparticles, 209.6 nm in size, with a negatively charged zeta potential. The AANCP exhibited better stability in four plasma samples (human, dog, rat, and mouse) and was slowly released in different pH conditions (pH 2.0, 7.4, and 8.0) compared with non-complexedABF. In vitro studies on microglial cells treated with AANCPs revealed a suppression of inflammatory cytokines (tumor necrosis factor-alpha and interleukin-6) induced by LPS. The AANCP increased microglial Aβ phagocytosis through the activation of triggering receptor expressed on myeloid cell 2 (TREM2)-related microglial polarization. The AANCP inhibited aggregation of Aβ in vitro and alleviated cognitive impairment in a scopolamine-induced in vivo dementia mouse model. Conclusions: Our data indicate that AANCPs are more stable than ABFs and effective for cognitive disorders and neuroinflammation via modulation of M2 microglial polarization.

Exploring the Therapeutic Promise of Melittin: Anti-Inflammatory and Anti-Cancer Applications of Bee Venom

Bee venom, a complex mixture of bioactive components, has garnered attention for its therapeutic properties, with melittin identified as its primary active component. This review highlights the potential of melittin in treating inflammation and cancer, two major health challenges. Inflammatory diseases, characterized by dysregulated immune responses, benefit from melittin's anti-inflammatory effects, including the inhibition of pro-inflammatory cytokines and activation of anti-inflammatory signaling pathways. Both preclinical and clinical studies have demonstrated melittin's ability to reduce inflammation across various disease models. In oncology, melittin has shown promising anti-cancer effects by inhibiting cell proliferation and inducing apoptosis in cancer cells. Recent evidence suggests melittin's efficacy against breast cancer and its potential application in other malignancies, such as prostate, colorectal, and pancreatic cancers. Additionally, melittin enhances the effectiveness of conventional treatments like chemotherapy and radiation. Despite its therapeutic promise, the potential toxicity and adverse effects of melittin necessitate careful investigation. Current research focuses on strategies to mitigate toxicity and improve its safety profile. This review underscores the significant progress in understanding melittin's mechanisms of action and therapeutic potential, emphasizing the need for further studies to develop safe and effective melittin-based treatments for inflammatory and cancerous diseases.

Respiratory Protective Effects of Perilla Leave Varieties (Perilla frutescens) Against Fine Particulate Matter (PM2.5)-induced Damage in Human Nasal Cells.

Fine particulate matter (PM2.5) is known to exacerbate chronic respiratory disorders, primarily by inducing inflammatory responses and mucus overproduction. Perilla leaves are reported to have significant health benefits, such as antioxidant, antibacterial, and antiallergic properties, attributed to phenolic compounds that vary depending on genetic diversity. In this study, flavonoid-rich extracts (FRE) from 56 perilla leaf varieties and genetic resources were prepared and screened using a mass screening system. The screening focused on evaluating their anti-inflammatory, mucus-reducing, and respiratory protective effects against PM2.5-induced damage in human nasal cells (RPMI2650). Parameters such as cell viability, nitric oxide (NO) levels, and mucus secretion factor (MUC5AC) concentrations were assessed. Among the 56 varieties, Perilla frutescens var. crispa (YCPL706), sourced from Ulleung Island, Korea, exhibited the highest cell viability (112.50%, 100 μg/mL), lowest NO concentration (9.98 μM, 100 μg/mL), and MUC5AC level (78.65 ng/mL, 100 μg/mL). Further evaluation of YCPL706 FRE demonstrated significant respiratory protective effects, including the inhibition of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), MUC5AC, and oxidative stress factors (MDA and ROS), compared to the control cultivar Namcheon. YCPL706 also showed strong antibacterial activity against Pseudomonas aeruginosa (minimum inhibitory concentration: 5 mg/mL). These findings suggest that the genetic resource YCPL706 is a promising candidate for combating PM2.5-induced respiratory damage due to its potent anti-inflammatory, antioxidant, and antibacterial properties.

Potentiating CAR-T-cell function in the immunosuppressive tumor microenvironment by inverting the TGF-β signal.

The immunosuppressive tumor microenvironment represents a key challenge for chimeric antigen receptor (CAR) T cells in solid tumors and includes the production of the inhibitory cytokine transforming growth factor-β (TGF-β), which limits CAR-T-cell persistence and function. Current strategies involving the blockade of TGF-β signaling have little benefit for solid tumor treatment. Here, we demonstrate a novel inverted cytokine receptor (ICR)-modified CAR-T-cell strategy not only TGF-β signal blockade but also antitumor efficacy enhancement. The newly designed T cells carry an ICR construct that fuses the TGF-β receptor II extracellular domain to the interleukin-15 (IL-15) receptor α cytoplasmic domain (named TB15) and is directed to the tumor antigen epidermal growth factor receptor by a CAR construct. In mice with high-TGF-β solid tumors, our signal-inverted CAR/TB15 T cells effectively treat tumors by blocking TGF-β and repurposing IL-15 stimulative signaling, resulting in enhanced CAR-T-cell persistence and function. As a proof of concept, our study results extend synthetic receptor signaling beyond CAR-directed killing, which could endow adoptively transferred T cells with new functions that overcome major barriers in the treatment of solid tumors by using a chimeric inverted cytokine receptor.

CD8+ T cell exhaustion in the tumor microenvironment of breast cancer

CD8+ T cells are crucial cytotoxic components of the tumor immune system. In chronic inflammation, they become low-responsive, a state known as T cell exhaustion (TEX). The aim of immune checkpoint blockade is to counteract TEX, yet its dynamics in breast cancer remain poorly understood. This review defines CD8+ TEX and outlines its features and underlying mechanisms. It also discusses the primary mechanisms of CD8+ TEX in breast cancer, covering inhibitory receptors, immunosuppressive cells, cytokines, transcriptomic and epigenetic alterations, metabolic reprogramming, and exosome pathways, offering insights into potential immunotherapy strategies for breast cancer.

Natural killer cells as promising candidates in Cancer therapeutics and related immune resistance in tumor microenvironment

Natural killer (NK) cells, as critical components of the innate immune system, have emerged as promising candidates in cancer therapy due to their ability to recognize and destroy tumor cells without prior sensitization. Their mechanisms of action, including perforin-granzyme release and antibody-dependent cellular cytotoxicity (ADCC), position them as versatile agents in cancer immunotherapy. Recent advancements, such as chimeric antigen receptor (CAR)-NK cells and cytokine-based stimulation, have demonstrated enhanced efficacy and reduced side effects compared to conventional immunotherapies. However, the immunosuppressive tumor microenvironment (TME) remains a significant obstacle, imposing challenges like immune checkpoint activation, cytokine suppression, and metabolic constraints that impair NK cell activity. This paper explores the therapeutic potential of NK cells, the challenges of immune resistance in the TME, and emerging strategies to enhance NK cell efficacy. Addressing these challenges is crucial for optimizing NK cell-based treatments and achieving durable responses in cancer patients.

Metabolomics and network pharmacology-guided analysis of TNF-α expression by Argemone mexicana (Linn) targeting NF-kB the signalling pathway in cancer cell lines.

Cancer has emerged as one of the leading causes of fatality all over the world. Phytoconstituents are being studied for their synergistic effects, which include disease prevention by altering molecular pathways and immunomodulation without side effects. The present experiment aims to explore the cancer preventive activities of Argemone mexicana Linn leaves extract in skin cancer cell lines (A431) and colon cancer cell lines (COLO 320DM)). In addition, TNF-α expression patterns and NF-kB signaling pathways have been examined. LC/MS study of Argemone mexicana Linn extracts in various solvents revealed anti-cancerous phytoconstituents. Network pharmacology analysis used Binding DB, STRING, DAVID, and KEGG for data mining to evaluate predicted compounds using functional annotation analysis. Cytoscape 3.2.1 created "neighbourhood approach" and networks. The MNTD of these extracts was tested on L929 fibroblasts. Skin cancer (A431) and colon cancer (COLO 320DM) cell lines were tested for IC50 inhibition. Evaluation of TNF-α and NF-kB expression in cell culture supernatants and homogenates reveals anti-cancerous effects. LC-MS analysis of extracts predicted the presence of anticancer alkaloids Berberine, Atropine, Argemexicin, and Argemonin. In Network pharmacology analysis, enrichment was linked to the PI3-AKT pathway for both cancer types. MNTD was calculated at 1000μg/ml in L929. The ethanolic extract at 1000μg/ml significantly inhibited skin cancer cell proliferation by 67% and colon cancer cells by 75%. Ethanolic extract significantly reduced TNF-α expression in both cell lines (p<0.001), with the highest inhibition at 1000μg/ml. In TNF-α stimulated cell lines, 1000μg/ml ethanolic extract significantly reduced the regulation of the NF-kB pathway, which plays a role in cancer progression (p<0.001). Argemone mexicana Linn. known as 'swarnkshiri' in Ayurveda has been reported to be used by the traditional healers for the treatment of psoriasis and its anti-inflammatory and anti-cancerous properties, according to the Indian Medicinal Plant dictionary. In the experiment, the abatement in the expression of inflammatory cytokine TNF-α and inhibition of NF-kB transcription factor activation could be linked with the downregulation of cancer cell proliferation. The study revealed the anticancer activity of Argemone mexicana Linn in the cancer cell lines and paved a pathway for molecular approaches that could be explored more in In vivo studies.

IL-35 may prevent the exacerbation of aspiration pneumonia involving Porphyromonas gingivalis by suppressing IL-17 production.

Periodontitis was reported to be associated with aspiration pneumonia. However, the relationship between periodontitis and aspiration pneumonia remains unclear. This study investigated the virulence factor of Porphyromonas gingivalis, which exacerbates aspiration pneumonia, and the role of IL-35, an inhibitory heterodimeric cytokine of EBI3 and p35, in aspiration pneumonia using Ebi3 knockout (KO) mice. Aspiration pneumonia was induced by the intratracheal injection of Streptococcus pneumoniae and P. gingivalis culture supernatant (mixed infection). We used leupeptin to inhibit gingipain, a virulence factor of P. gingivalis. Four days after infection, lung tissues were collected for analyses. The percentage of interstitium in the group with mixed infection and leupeptin treatment was significantly reduced compared with the non-leupeptin administration group. Additionally, the percentage of interstitium in the field of Ebi3 KO mice was significantly increased compared with wild-type (WT) mice in mixed infection. IL-35 production in WT mice with mixed infection was significantly increased compared with the Control group. IL-17 production in Ebi3 KO mice was significantly increased compared with WT mice with mixed infection. These findings suggest that gingipain exacerbates aspiration pneumonia and that IL-35 may contribute to suppressing the exacerbation of aspiration pneumonia.

Practical application of melatonin for pancreas disorders: protective roles against inflammation, malignancy, and dysfunctions.

Melatonin, a hormone primarily produced by the pineal gland, exhibits a range of physiological functions that extend beyond its well-known role in regulating circadian rhythms. This hormone influences energy metabolism, modulates insulin sensitivity, and plays a significant role in controlling sleep patterns and food intake. Notably, melatonin is also synthesized in various peripheral organs, including the gastrointestinal system and pancreas, suggesting its function as a local hormone. The presence of melatonin receptors in the pancreas underscores its relevance in pancreatic physiology. Pancreatic disorders, such as diabetes mellitus (DM), pancreatitis, and pancreatic cancer, often stem from inflammatory processes. The majority of these conditions are characterized by dysregulated immune responses and oxidative stress. Melatonin's anti-inflammatory properties are mediated through the inhibition of pro-inflammatory cytokines and the activation of antioxidant enzymes, which help to mitigate cellular damage. Furthermore, melatonin has demonstrated pro-apoptotic effects on cancer cells, promoting cell death in malignant tissues while preserving healthy cells. Thus, melatonin emerges as a multifaceted agent with significant therapeutic potential for pancreatic disorders. Its ability to reduce inflammation and oxidative stress positions it as a promising adjunct therapy for conditions such as diabetes mellitus, pancreatitis, and pancreatic cancer. By modulating immune responses and enhancing cellular resilience through antioxidant mechanisms, melatonin not only addresses the symptoms but also targets the underlying pathophysiological processes associated with these disorders. This review aims to categorize and summarize the impacts of melatonin on pancreatic functions and disorders, emphasizing its potential as a therapeutic agent for managing pancreatic dysfunctions. Future research should focus on elucidating the precise mechanisms by which melatonin exerts its protective effects on pancreatic tissues and exploring optimal dosing strategies for clinical applications. The integration of melatonin into treatment regimens may enhance existing therapies and offer new hope for individuals suffering from pancreatic dysfunctions.

Rhodiola rosea L. extract ameliorates ethanol-induced gastric ulcer in rats by alleviating oxidative stress and inflammation via NF-κB pathway inhibition

Rhodiola rosea L. is a traditional plant that has been found to exhibit a wide range of biological activities, however, there is a lack of research regarding its potential anti-ulcer activity. In this study, the plant’s anti-ulcer activity has been evaluated in detail for the first time. R. rosea methanolic extract anti-ulcer activity was investigated against ethanol-induced ulcer rats. The results showed that administering the extract to ulcerated rats reduced gastric acidity and ulcer index while improving nitric oxide (NO) and cytoprotective prostaglandin E2 (PGE2), as well as anti-oxidants glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). On the other hand, the extract decreased malondialdehyde (MDA) and myeloperoxidase (MPO) levels. Further, ELISA assays showed that R. rosea extract decreased pro-inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α levels in ulcerated rats. Western blot analysis confirmed the ELISA results, indicating that the extract decreased IL-6 and TNF-α protein expression and inhibited the NF-κB signalling pathway. Macroscopic and histological investigations on ulcerated rats verified the extract's anti-ulcer effects. The extract’s anti-ulcer activity was dose-dependent with the 600 mg/kg/day dose showing superior activity across all assays. GCMS analysis identified the extract’s major constituents as bicyclo [4.1.0] heptane, 7-pentyl (50.784 %) followed by 2-heptadecenal (33.2 %), and it is thought that these compounds play a crucial role in the extract’s bioactivity. Finally, in silico studies showed that the most abundant molecule, bicyclo [4.1.0] heptane, 7-pentyl, demonstrated the highest binding affinity in its interaction with H+, K+-ATPase. Taken together, the extract’s mode of action might include the inhibition of H+, K+-ATPase by bicyclo [4.1.0] heptane, 7-pentyl, followed by NF-κB pathway inhibition and subsequent regulation of cytokines and other inflammatory biomarkers. This innovative finding has the potential to lead to a successful anti-ulcer medicine, which might be followed by additional clinical trials or bioguided isolation research.

Cytokine release syndrome caused by immune checkpoint inhibitors: a case report and literature review.

Immune checkpoint inhibitors (ICIs) have gained widespread application in the treatment of malignant tumors. Cytokine release syndrome (CRS) is a systemic inflammatory response triggered by various factors, including infections and immunotherapy. We present a case of CRS occurring in a gastric cancer patient after receiving combination therapy of tislelizumab, anlotinib and combination of capecitabine and oxaliplatin. Nineteen days after the third dose of tislelizumab, the patient experienced sudden unconsciousness, frothing at the mouth, convulsions and other clinical manifestations resembling epileptiform seizures. Elevated inflammatory markers, cytokine levels and ferritin were markedly increased. Given the absence of definite clinical evidence for metastasis and infection, the diagnosis of CRS was considered. Subsequent management with glucocorticoids and intravenous immunoglobulin resulted in the patient's improvement. However, antitumor therapy was halted, ultimately leading to death. The administration of ICIs can incite CRS, a severe, rapidly progressing condition with a poor prognosis, demanding clinical attention. Cytokines play a dual role in the pathophysiology of immune-related adverse events by mediating self-tolerance attenuation and enhancing the activation of cytotoxic T cells in the antitumor process of ICIs. The therapy of glucocorticoids combined with cytokine inhibitors may become an effective remedy.

Inhibition of pro-inflammatory cytokines by homalolide A and homalomenol A isolated from rhizomes of Homalomena pendula.

Inflammation, a natural process of the innate immune system, involves elevated levels of various proinflammatory mediators, such as, nitric oxide (NO) and prostaglandin (PGE2), cytokines such as interleukin 6 (IL-6), interleukin 10 (IL-10) and tumor necrosis factor alpha (TNF-α), and enzymes including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). This study investigated the anti-inflammatory effects of homalolide A (1) and homalomenol A (2), two sesquiterpenoids isolated from the rhizome of Homalomena pendula, on lipopolysaccharide (LPS)- stimulated macrophage cells. The results demonstrated that both 1 and 2 dose-dependently inhibited the production of PGE2, TNF-α and IL-6 in RAW 264.7 macrophages. Furthermore, 2 also stimulated IL-10 production in RAW 264.7 cells. Consistent with these findings, these compounds suppressed the LPS-stimulated protein levels of iNOS and COX-2 in RAW 264.7 cells. These results suggested that 1 and 2 could be effective candidates for ameliorating inflammatory-associated complications.

Interleukin-6: Cardiovascular Aspects of Long-Term Cytokine Suppression in Patients with Rheumatoid Arthritis.

In recent years, many atherogenesis researchers have focused on the role of inflammatory cytokines in the development of cardiovascular disease (CVD). Interleukin-6 (IL-6) cytokine is independently associated with higher CVD risk in patients with rheumatoid arthritis (RA). The effect of IL-6 inhibitors on the cardiovascular system in RA patients remains poorly understood, especially with its long-term use. This study investigates the effect of therapy with IL-6 receptor blocker tocilizumab (TCZ) on the dynamics of cardiovascular risk (CVR), modifiable risk factors (RFs), carotid artery (CA) structural changes, and the incidence of cardiovascular complications (CVCs) in RA patients during a 265-week follow-up period. Forty-five patients with active RA (DAS28-ESR 6.2 (5.5;6.8) with ineffectiveness and/or intolerance to disease-modifying antirheumatic drugs (DMARDs) were included in this study. During long-term therapy with TCZ in RA patients, no increase in CVR and no significant structural changes in CA were observed. No significant changes in the blood lipid spectrum were observed in patients without statin therapy. In the group of patients receiving statins, there was a 43% increase in high-density lipoprotein cholesterol (HDL-C), a 15% reduction in total cholesterol levels, and a 56% decrease in the atherogenicity index (p < 0.01 in all cases). Associations were found between ∆ total cholesterol and ∆ C-reactive protein (CRP) (R = 0.36, p = 0.04), ∆ low-density lipoprotein cholesterol (LDL-C), and ∆-CRP (R = 0.42, p = 0.03) in RA patients receiving statins. Initially, the thickness of the intima-media complex of carotid arteries (cIMT) positively moderately correlated with age (R = 0.7; p < 0.01), BMI (R = 0.37; p < 0.01), and systolic blood pressure (R = 0.64; p < 0.01); however, it weakly correlated with the lipid spectrum parameters: total cholesterol (R = 0.29; p < 0.01) and LDL-C (R = 0.33; p < 0.01). No new associations of cIMT by the end of the follow-up period, as well as the relationship of cIMT value with RA activity and therapy, were revealed. Patients with carotid ASPs showed an oppositely directed relationship between total cholesterol and sVCAM-1 at baseline (R = -0.25, p = 0.01) and at the end of this study (R = 0.29, p < 0.01). The incidence of cardiovascular events was 0.53 per 100 patient-years during the 265-week period of TCZ therapy.

Design and synthesis of C-17 benzylidene derivatives of 14-deoxyandrographolide (14-DAG) and their TNF-α and IL-6 expression inhibitory activities

Benzylidene derivatives of 14-deoxyandrographolide (14-DAG) have been synthesised in good to excellent yield. All the synthesised compounds were screened for anti-inflammatory activity. The results of the cell viability assay suggested that most of the compounds were non-toxic and were further selected for investigation of NO inhibition potential. The selected compounds were investigated for their NO inhibition potential in comparison to andrographolide using LPS induced RAW 264.7 cells. The results demonstrated significant NO inhibitory activity of compound 4e in comparison to andrographolide. Based on these results, compound 4e was further investigated for inhibition of pro-inflammatory cytokines, including cytokines TNF-α and IL-6 in LPS-induced murine macrophages. Inhibitory effects of compound 4e, on pro-inflammatory cytokines TNF-α and IL-6 were compared to the parent compound, andrographolide, wherein the results demonstrated that compound 4e exhibited an IC50 (TNF- α) of 8.07 µM in comparison to andrographolide which exhibited an IC50 of 15.86 µM. Further molecular docking studies of the most potent compound 4e was also performed, which showed that the chemical forms substantial hydrogen and alkyl bonds with TNF-α, demonstrating a greater binding affinity than IL-6. The overall findings of compound 4e suggested that it can possibly be a promising structural lead for the development of new anti-inflammatory agents.

Jinwu Jiangu Capsule alleviates rheumatoid arthritis symptoms by regulating the ADCY10 and cAMP/RANKL pathways

Ethnopharmacological relevanceRheumatoid arthritis (RA) is a systemic autoimmune disease that primarily affects joints and damages other tissues, including the heart, kidneys, lungs, digestive system, eyes, skin and nervous system. Jinwu Jiangu Capsule (JWJG) is effective in tonifying kidneys, activating blood circulation, and dispelling wind and dampness. Meanwhile, it produces favorable clinical results in relieving joint pain and reducing inflammation. However, precise therapeutic effect and mechanisms of JWJG on RA remain unclear. Aim of the studyThe traditional Chinese medicine JWJG exhibits certain properties in anti-inflammation and pain relief for RA treatment. This study aimed to investigate the efficacy of JWJG and elucidate its underlying mechanisms in RA treatment. Materials and methodsA collagen-induced arthritis (CIA) rat model was administered JWJG orally at varying doses for 28 days, alongside control and positive control groups treated with saline and leflunomide, respectively. Indicators including joint swelling, bone loss, histopathological changes, Th17/Treg lymphocyte differentiation, and inflammatory factor expression were assessed. RNA sequencing of synovial tissues identified JWJG-influenced genes and pathways. RASFs treated with ADCY10 lentivirus, PKA agonist, or AR plasmid underwent additional JWJG-containing serum or β-sitosterol treatment to monitor ADCY10, RANKL, and cAMP pathway alterations. ResultsJWJG administration significantly reduced joint swelling, bone loss, and inflammation, balanced Th17/Treg, and suppressed TNF-α, IL-1β, IL-6, and RANKL levels. In RASFs, JWJG downregulated ADCY10, cAMP, and phospho-PKA/CREB, thereby inhibiting osteoclast differentiation. Meanwhile, β-sitosterol decreased AR levels, which suppressed ADCY10 and RANKL expression. JWJG treatment could directly/indirectly inhibit ADCY10 reduced cAMP/RANKL, inflammation, and osteoclastogenesis, enhancing RA symptomatology comparable to leflunomide. It demonstrated superior regulation of Th17/Treg ratios and cytokine suppression, with potential to substantially improve RA patients’ quality of life. ConclusionsJWJG inhibited ADCY10, decreased cAMP/RANKL, and impeded inflammation and osteoclastogenesis, with a notable improvement in RA symptoms comparable to leflunomide. It can be introduced as a potential new therapeutic strategy for preventing or even reversing bone damage and improving the quality of life for RA patients.