IL-1beta Research Articles

Comparison of Early-Stage Knee Osteoarthritis Induced by Medial Meniscus Tear Versus Tibial Osteotomy in the Rat Model.

Medial meniscus tear (MMT) is a common method to induce osteoarthritis in rats, but mimics secondary osteoarthritis. A novel method of carrying out a medial wedge closing tibial osteotomy (TO) has been recently developed to induce primary osteoarthritis. This study aims to validate it, compared to MMT. Twenty rats were divided equally into 2 groups. Outcome measures such as histology graded according to Osteoarthritis Research Society International (OARSI) guidelines and computed tomography (CT) scans were analyzed at 6 weeks post-operatively. Observational gait analysis and serum biomarkers such as C-terminal cross-linked telopeptides of type II collagen (CTX-II) and interleukin-1 beta (IL-1β) were collected at 2-weekly intervals up to 6 weeks post-operatively. Serum CTX-II and IL-1β levels did not reveal a statistically significant difference across all time points between the 2 groups. CT grading was significantly more severe (2.80 ± 1.10 vs 1.40 ± 0.548, P = 0.0389) in the MMT group compared to the TO group. In addition, histological gradings such as calcified cartilage score (2.10 ± 1.91 vs 0.00 ± 0.00, P < 0.01) and cartilage degeneration score (4.80 ± 5.18 vs 0.00 ± 0.00, P < 0.01) revealed significantly more severe osteoarthritis in the MMT compared to TO group. Synovial membrane score did not reveal a statistically significant difference (1.10 ± 0.994 vs 1.00 ± 0.00, P = 1.00). TO is a novel method in inducing primary osteoarthritis in the rat model compared to MMT between the 6 and 12 weeks' time frame.

Identification and Analysis of Autophagy-Related Genes as Diagnostic Markers and Potential Therapeutic Targets for Tuberculosis Through Bioinformatics.

According to the World Health Organization, Mycobacterium tuberculosis infections affect approximately 25% of the world's population. There is mounting evidence linking autophagy and immunological dysregulation to tuberculosis (TB). As a result, this research set out to discover TB-related autophagy-related biomarkers and prospective treatment targets. We used five autophagy databases to get genes linked to autophagy and Gene Expression Omnibus databases to get genes connected to TB. Then, functional modules associated with autophagy were obtained by analyzing them using weighted gene co-expression network analysis. Both Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were used to examine the autophagy-related genes (ATGs) of important modules. Limma was used to identify differentially expressed ATGs (DE-ATGs), and the external datasets were used to further confirm their identification. We used DE-ATGs and a protein-protein interaction network to search the hub genes. CIBERSORT was used to estimate the kinds and amounts of immune cells. After that, we built a drug-gene interaction network and a network that included messenger RNA, small RNA, and DNA. At last, the differential expression of hub ATGs was confirmed by RT-qPCR, immunohistochemistry, and western blotting. The diagnostic usefulness of hub ATGs was evaluated using receiver operating characteristic curve analysis. Including 508 ATGs, four of the nine modules strongly linked with TB were deemed essential. Interleukin 1B (IL1B), CAPS1, and signal transducer and activator of transcription 1 (STAT1) were identified by intersection out of 22 DE-ATGs discovered by differential expression analysis. Research into immune cell infiltration found that patients with TB had an increased proportion of plasma cells, CD8 T cells, and M0 macrophages. A competitive endogenous RNA network utilized 10 long non-coding RNAs and 2 miRNAs. Then, the IL1B-targeted drug Cankinumad was assessed using this network. During bioinformatics analysis, three hub genes were validated in mouse and macrophage infection models. We found that IL1B, CASP1, and STAT1 are important biomarkers for TB. As a result, these crucial hub genes may hold promise as TB treatment targets.

Acetyl tributyl citrate attenuates 5-fluorouracil-induced inflammation, oxidative stress, and apoptosis in human keratinocytes

5-Fluorouracil (5-FU) is a commonly used chemotherapy drug that effectively destroys cancer cells. Despite its widespread use and efficacy, it also presents considerable challenges, particularly with adverse effects on rapidly dividing normal cells, such as keratinocytes. These detrimental effects are attributed to inflammatory, oxidative, and apoptotic potentials, leading to severe skin disorders. Due to the lack of specific remedies for 5-FU-induced dermatological side effects, conventional treatments are applied instead, which provide limited relief and have drawbacks. This study investigated the impact of acetyl tributyl citrate (ATBC) in 5-FU-treated human keratinocytes. The findings indicated that ATBC substantially reduced inflammation caused by 5-FU, as demonstrated by nuclear translocation of nuclear factor kappa B and expression of its downstream genes, including tumor necrosis factor, interleukin 1 beta (IL1B), and IL6. ATBC also markedly decreased oxidative stress, indicated by reactive oxygen species levels and the antioxidant gene expression such as superoxide dismutase 1 (SOD1), SOD2, and heme oxygenase 1 in 5-FU-treated cells. Furthermore, ATBC attenuated 5-FU-induced apoptosis, as determined by lactate dehydrogenase release and Annexin V/propidium iodide flow cytometry, with the potential involvement of interferon-related genes. Following this, protein kinase C delta was predicted as a possible molecular target of ATBC. These findings propose ATBC as a therapeutic agent for managing the cutaneous side effects associated with 5-FU treatment.

Small molecule inhibitors of IL-1R1/IL-1β interaction identified via transfer machine learning QSAR modelling

The human interleukin-1 receptor I (IL-1R1) is a cytokine receptor recognized by interleukin 1β (IL-1β), among other cytokines. Over activation of IL-1R1 has been implicated in various inflammatory conditions. This research aims to identify small-molecule inhibitors targeting the hIL1R1/IL1β interaction, employing a multi-task transfer learning approach for quantitative structure-activity relationship (QSAR) modelling. A comprehensive bioactivity dataset from functionally related proteins was utilised to build a robust ensemble machine learning model for predicting IC50 values against the target protein. Despite the availability of antibody-based therapies, the absence of orally available small-molecule inhibitors necessitates their development. By combining model predictions with docking and simulation approaches, the interleukin-1 receptor inhibitor (IRI-1) emerged as a lead compound. It potently inhibited human IL1-R1 with micromolar activity in THP-1 and Saos-2 cells and demonstrated good biocompatibility. Western blot analysis revealed that IRI-1 inhibits IL-1β-mediated phosphorylation of IL1-R1, JNK, IRAK-4, and ERK in THP-1 cells. Furthermore, molecular dynamics simulations confirmed the structural stability of the protein-ligand complexes. This study highlights the effectiveness of multi-task transfer learning approaches for building robust QSAR models against novel proteins or those with limited bioactivity data, such as hIL-1β/IL-1R1 protein.

Tempol mitigates inflammation, oxidative stress, and histopathological alterations of cadmium-induced parotid gland injury in rats

Cadmium (Cd) is a potent environmental pollutant that causes functional and structural damage to the salivary glands. Tempol (TEM) has powerful antioxidant activity that can potentially preserve organ function. Aims: This study was designed to investigate the protective effects of TEM on Cd-induced toxicity in rat parotid salivary glands. Materials and methods: Twenty-four adult Wistar male rats were randomly assigned to four equal groups: control, TEM (27.5 g/100 ml), Cd (0.6 g/100 ml), and TEM plus Cd (at the same doses). All treatments were dissolved in distilled water and administered subcutaneously four times a week for four weeks. Parotid gland tissues were isolated and subjected to molecular and histo-biochemical assessments. Key findings: TEM exerted a prophylactic effect against Cd-induced toxicity in the parotid glands by controlling inflammation through the downregulation of toll-like receptor 4/myeloid differentiation primary response 88/nuclear factor kappa B/ interleukin-1 beta mRNA expression, upregulation of aquaporin-5 mRNA expression, improvement of the oxidant/antioxidant status in the parotid gland, mitigation of endoplasmic reticulum stress, and repair of the associated histological and ultrastructural abnormalities. Significance: TEM protects against Cd-induced toxicity in the parotid glands of rats, attributable at least in part to its anti-inflammatory and antioxidant properties, as well as its ability to inhibit ER stress and facilitate glandular repair. However, the protective effects of TEM did not reach the levels observed in the control group. TEM could be a promising clinical candidate for protecting the salivary glands, particularly in high-risk groups such as workers exposed to Cd and cigarette smokers.

The Antinociceptive Effects and Sex-Specific Neurotransmitter Modulation of Metformin in a Mouse Model of Fibromyalgia

Fibromyalgia (FM) is a chronic and debilitating condition characterized by diffuse pain, often associated with symptoms such as fatigue, cognitive disturbances, and mood disorders. Metformin, an oral hypoglycemic agent, has recently gained attention for its potential benefits beyond glucose regulation. It has shown promise in alleviating neuropathic and inflammatory pain, suggesting that it could offer a novel approach to managing chronic pain conditions like FM. This study aimed to further explore metformin’s analgesic potential by evaluating its effects in an experimental FM model induced by reserpine in both male and female mice. After the administration of 200 mg/kg metformin to male and female mice, the FM-related symptoms were assessed, including mechanical allodynia, thermal hyperalgesia, and depressive-like behaviors. A histological examination of the thalamus, hippocampus, and spinal cord was conducted using haematoxylin and eosin staining. The neurotransmitter and proinflammatory cytokines levels were measured in the brains and spinal cords. Our results have shown that metformin treatment for seven days significantly reversed these FM-like symptoms, reducing pain sensitivity and improving mood-related behaviors in both the male and female mice. Additionally, metformin exhibited neuroprotective effects, mitigating reserpine-induced damage in the hippocampus, thalamus, and spinal cord. It also significantly lowered the levels of the proinflammatory cytokine interleukin 1-beta (IL-1β) in the brain and spinal cord. Notably, metformin modulated the neurotransmitter levels differently between the sexes, decreasing glutamate and increasing serotonin and norepinephrine in the male mice, but not in the females. These findings underscore metformin’s potential as an alternative therapy for FM, with sex-specific differences suggesting distinct mechanisms of action.

Potential Effect of Etoricoxib in Reducing Inflammation in Methotrexate-Induced Pulmonary Injury in Rats: Role of Oxidative Stress and the TLR4/p38-MAPK/NF-κB Signaling Pathway.

Numerous chemotherapeutic medications can have hazardous effects on the lungs, which can result in severe lung diseases. Methotrexate (MTX) is prescribed for cancer and inflammation-related disorders; nevertheless, it is exceptionally highly toxic and has multiple kinds of adverse reactions, including pulmonary injury. Our work was designed to demonstrate the ability of etoricoxib (ETO) to mitigate MTX-induced lung injury in experimental animals. Adult male Wistar rats were separated into four groups. The first group consisted of healthy controls that received carboxymethyl cellulose (1 ml/day, p.o.), the second group received a single dose of MTX (20 mg/kg/day, i.p.), the third group received ETO (10 mg/kg/day, p.o.) for three weeks, and the fourth group first received a single MTX (20 mg/kg, i.p.) and then was treated with ETO for three weeks. Concomitant treatment with ETO and MTX improved the histological structure of the lung tissue. It significantly altered the levels of oxidant/antioxidant markers, such as malondialdehyde (MDA), heme oxygenase-1 (HO-1), reduced glutathione (GSH), and nuclear factor erythroid 2-related factor 2 (Nrf-2), in favor of antioxidants. Moreover, ETO can normalize the proinflammatory cascade, which includes tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β). At the molecular level, ETO downregulated the protein expression of toll-like receptor 4 (TLR4), nuclear factor kappa-B (NF-κB), and p38 mitogen-activated protein kinase(p38 MAPK) in inflamed rat lungs. In conclusion, our findings indicate that oral administration of ETO ameliorates MTX-induced lung injury by inhibiting oxidative stress and suppressing the TLR4/NF-κB and TLR4/p38-MAPK inflammatory signaling pathways.

Mesenchymal stem cells treated with Interleukin-1 beta for mediation of an inflammatory response in human tissues.

The present study examined the functional activities of the human bone marrow mesenchymal stem cells (hBM-MSCs) under the effects of various concentrations of the inflammatory mediator interleukin 1 beta (IL-1β). The effects of IL-1β on the functional properties of hBM-MSCs were measured using functional assays (adhesion, proliferation, and migration). hBM-MSCs expressions of colony-stimulating factors 1 and 2 (CSF1, CSF2), C-C chemokine receptor type 2 (CCR2), C-X-C chemokine receptor type 1 and 3 (CXCL1, CXCL3), were examined using real-time polymerase chain reaction (RT‒PCR). The pro-inflammatory cytokine IL-1β did not disrupt hBM-MSCs adhesion, but it improved proliferation and migration only up to 50 ng/ml. However, in response to 100 ng/ml IL-1β, cell growth, proliferation, and migration were reduced significantly. The expression of CSF1, CCR2, CXCL3, and IL-1β genes increased with the increase in the concentration of IL-1β. CSF2 and CXCL1 gene expression increased in the 50ng/ml group compared with the 10ng/ml group to be higher than the control group in the 100ng/ml IL-1β group which might facilitate the differentiation, and homing of MSCs to the site of injury and augment their activities in the inflamed microenvironment. The study corroborates the advantages of prior stimulation of mesenchymal stem cells (MSCs) with the cytokine IL-1β, demonstrating an upregulation of key chemokines and cytokines. This upregulation potentially enhances MSCs' ability to differentiate and migrate to injury sites, while also augmenting their functional role within an inflamed microenvironment, thereby amplifying their therapeutic potential.

Paeonol inhibits ACSL4 to protect chondrocytes from ferroptosis and ameliorates osteoarthritis progression

BackgroundDiscovering an inhibitor for acyl-CoA synthetase long-chain family member 4 (ACSL4), a protein that triggers cell injury via ferroptosis, presents potential to minimize cellular damage. This study investigates paeonol (PAE), a traditional Chinese herbal medicine, as an ACSL4 inhibitor to prevent chondrocyte ferroptosis and protect against osteoarthritis (OA). MethodsWe conducted in vitro experiments using mouse chondrocytes treated with PAE to mitigate ferroptosis induced by Interleukin-1 Beta (IL-1β) or ferric ammonium citrate (FAC), examining intracellular ferroptotic indicators, cartilage catabolic markers, and ferroptosis regulatory proteins. A mouse OA model was created via destabilized medial meniscus (DMM), followed by intra-articular PAE injections. After 8 weeks, micro-computed tomography and histological assessments evaluated PAE's protective and anti-ferroptotic effects in the OA model. ResultsIn vitro results showed PAE significantly reduced IL-1β/FAC-induced damage by targeting ACSL4, including cell apoptosis, inflammatory responses, extracellular matrix degradation, and ferroptotic markers (oxidative stress, lipid peroxidation, and iron buildup). It also restored the expression of ferroptotic suppressors and mitigated mitochondrial damage. Additionally, PAE increased cartilage anabolic marker expression while reducing cartilage catabolic marker expression. Molecular docking, cellular thermal shift assay, and drug affinity responsive target stability analysis verified the binding interaction between PAE and ACSL4. Furthermore, the role of PAE in chondrocytes was further verified through ACSL4 knockdown and overexpression. In vivo, mice with OA showed increased cartilage degradation and ferroptosis, while intra-articular PAE injection alleviated these pathological changes. ConclusionPAE significantly protects chondrocytes from ferroptosis induced by IL-1β/FAC in primary mouse chondrocytes and DMM surgery-induced OA mice through ACSL4 inhibition. The translational potential of this articleThese findings highlight the potential of targeting ACSL4 in chondrocytes as a treatment strategy for OA, positioning PAE as a promising drug candidate.

Effect of periodontal therapy on serum and salivary Interleukin-1 beta (IL-1β) and malondialdehyde levels in chronic periodontitis.

Chronic periodontitis (CP) is distinguished by an inflammatory reaction and the presence of oxidative stress (OS), which has consequences for overall health. Interleukin-1β (IL-1β) and malondialdehyde (MDA) serve as markers of inflammation and OS, respectively. Analyzing the alterations in their reaction to periodontal therapy can provide valuable insights into the management and monitoring of CP progression. The current study aimed to evaluate the impact of non-surgical periodontal therapy (NST) on IL-1β and MDA levels in the serum and saliva of CP patients and explore their correlation with clinical periodontal indices post-therapy. There were 60 participants in this research, aged 33 to 50, equally split between thirty periodontally healthy controls and 30 patients with CP. Measures were taken of the clinical periodontal parameters, including the bleeding index, probing pocket depth, gingival index, and plaque index. Saliva and blood samples were collected for IL-1β and MDA analysis using ELISA and spectrophotometrically. CP patients received scaling and root planning (SRP) as part of phase I periodontal therapy, and after six weeks, we reevaluated clinical parameters and IL-1β and MDA levels. In CP patients, both saliva and serum IL-1β and MDA levels significantly increased alongside worsening clinical periodontal parameters compared with periodontally healthy individuals. phase I periodontal therapy led to a notable decrease in both saliva and serum IL-1β and MDA levels, accompanied by improvements in clinical parameters. Additionally, following six weeks of scale and root planning treatment, our data showed a strong positive relationship between salivary IL-1β and MDA levels with PPD and CAL. SRP therapy is effective in managing periodontal health, as evidenced by a significant decrease in clinical parameters and biomarker levels after treatment for CP patients. This suggests that salivary IL-1β and MDA may be useful biomarkers for indicating the severity of periodontal disease and the effectiveness of treatment.

IL-17A is a key regulator of neuroinflammation and neurodevelopment in cognitive impairment induced by sevoflurane

Increasing numbers of animal studies have shown that repeat sevoflurane exposure during developmental stage may lead to long-term cognitive impairment. Nevertheless, the exact pathogenesis remains unclear. Interleukin 17A (IL-17A) has been associated with cognitive decline in various neurological disorders. Here we found that the expression of IL-17A was up-regulated in hippocampus of sevoflurane exposed neonatal mice. Genetic deletion of IL-17A or inhibition of IL-17A improved behavioral function and down-regulated neuroinflammation related genes, interleukin 1β (IL-1β), interleukin 6 (IL-6), Nicotinamide adenine dinucleotide phosphate(NADPH) oxidase 2 (NOX2) and NADPH oxidase 4 (NOX4) in hippocampus of sevoflurane exposed neonatal mice. Moreover, negative regulation of IL-17A/Interleukin 17A receptor(IL-17RA) promoted the extracellular signal-regulated protein kinase (ERK) signaling pathway and nucleation of cyclic adenosine monophosphate (cAMP) response element-binding (CREB) in neurons of cognitive impaired mice. Knockdown of IL-17A in vivo identified neurons-localized IL-17A as a major factor in neuroinflammation and neurodevelopment. Collectively, our results suggested that IL-17A was required for the pathogenesis of neuroinflammatory response and identify IL-17A as a potential therapeutic target for cognitive impairment exposed by general anesthetics during infancy.

Exploration of the molecular mechanism of Wufu Yin in the treatment of knee osteoarthritis based on network pharmacology and experimental validation

Wufu Yin (WFY) exhibits significant clinical effectiveness in knee osteoarthritis (KOA) treatment, yet its therapeutic mechanisms are still unclear. This study aimed to explore the active ingredients and potential mechanism of WFY in the treatment of KOA. The network pharmacology-based approach was adopted to investigate the underlying mechanism of WFY in treating KOA. Molecular docking analysis was performed using Auto Vina software. An in vitro model of KOA inflammation was established by inducing chondrocyte cultures with interleukin-1 beta (IL-1β). Cell viability was quantified through the cell counting kit-8 assay, inflammatory cytokine levels were measured via ELISA, and protein expressions were assessed by Western blot analysis. A total of 225 active ingredients and 265 targets of WFY were identified, of which 88 were identified as potential targets against KOA. Enrichment analysis showed that these targets were associated with oxidative stress, cell proliferation and apoptosis, and inflammatory response, and were involved in the regulation of Th17 cell differentiation, IL-17 signaling pathway, tumor necrosis factor signaling pathway, and other signaling pathways. Topology analysis showed that PTGS2, NOS2, ESR11, PPARG, and MAPK14 had higher degree values and were key targets of WFY in the treatment of KOA. Molecular docking analysis showed that these key targets and active ingredients had low binding energies, indicating that they had potential binding activity. Furthermore, IL-1β-induced elevation of inflammatory cytokines, PTGS2 protein expression, and phosphorylated p38/p38 ratios in chondrocytes were significantly attenuated upon WFY intervention. Our study systematically elucidated the pharmacological basis and molecular mechanism underlying WFY’s therapeutic effects in KOA, substantiating its ability to suppress inflammation and regulate PTGS2 expression and p38 phosphorylation.

Luteal fibroblasts produce prostaglandins in response to IL1β in a MAPK-mediated manner

The corpus luteum is a temporary endocrine gland that is crucial for pregnancy, as it produces the progesterone needed to maintain optimal uterine conditions for implantation. In the absence of a conceptus, the corpus luteum becomes non-functional and undergoes rapid tissue remodeling to regress into a fibrotic corpus albicans. Early luteal regression is characterized by increased cytokine release. Because the role of fibroblasts in the bovine corpus luteum remains to be elucidated, the aim of this study was to elucidate the response of bovine luteal fibroblasts to inflammatory cytokines, tumor necrosis factor α (TNFα), and interleukin 1β (IL1β). Both cytokines induced canonical mitogen activated protein kinase (MAPK) signaling in luteal fibroblasts by phosphorylation of ERK1/2, p38 MAPK, and JNK. IL1β elevated expression and phosphorylation of cytosolic phospholipase A2 (cPLA2), an enzyme that mobilizes arachidonic acid for prostanoid synthesis. IL1β also elevated expression of prostaglandin-endoperoxide synthase 2 (PTGS2), another enzyme needed to synthesize prostanoids. IL1β increased PGF2α and PGE2 levels in the culture medium over 20-fold. Inhibition of MAPKs with small-molecule inhibitors abrogated the stimulatory effects of IL1β. IL1β also induced prostaglandin production in steroidogenic cells; however, there was no elevation in cPLA2. Therefore, actions of IL1β differ based on ovarian cell type. All together, we have identified luteal fibroblasts as potential inflammatory mediators during luteal regression.

Comparison of Biomarkers Playing a Role in Pterygium Development in Pterygium and Recurrent Pterygium Tissues

Background/Objectives: Pterygium is a nonneoplastic elastotic degeneration characterized by subepithelial growth. It manifests as an ocular lesion originating from the bulbar conjunctiva, extending to the corneal surface, and reaching the visual axis in some cases. Although the exact cause is unknown, prolonged exposure to ultraviolet radiation is considered the most significant contributing factor. Chronic irritation and actinic damage are likely responsible for the typical fibrovascular reactions observed in pterygium. Additionally, growth factors, cytokines, and matrix metalloproteinases play roles in the pathogenesis of pterygium. This study compared recurrent and primary pterygium cases at the molecular level to gain new insights into the etiology of pterygium. Methods: Total protein was extracted from surgical samples of patients with primary and recurrent pterygium, and the levels of transforming growth factor beta 1 (TGF-β1), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), IL-8, and IL-10 were analyzed using the enzyme-linked immunosorbent assay technique. Target gene expression levels were analyzed using the ΔΔCt method after cDNA synthesis from isolated RNA, with normalization to GAPDH and quantification performed with SYBR Green PCR Master Mix. Results: Among the studied cytokines, IL-10 levels were higher in primary pterygium than in recurrent pterygium (722.0 ± 600.9/421.4 ± 266.8) (p = 0.0054). Other cytokines (IL-6, IL-8, IL-1β, and TGF-β1) were detected at similar levels in both primary and recurrent pterygium (p = 0.2986). Additionally, the TGF-β1 gene expression was found to be significantly upregulated in recurrent pterygium tissue compared to primary pterygium tissue (p = 0.034). Conclusions: This increase suggests that TGF-β1 may contribute to the recurrence mechanisms of pterygium through processes such as fibroblast activation and tissue remodeling. The higher levels of IL-10 in primary pterygium compared to recurrent pterygium indicate an enhanced early protective response aimed at limiting pterygium progression and controlling the inflammatory process.

Pathological effects and immune modulation in host during Tilapia Parvovirus (TiPV) outbreak in cage and wetland Tilapia farms.

Viral diseases arising in farmed fish are an ongoing challenge to the aquaculture industry, causing severe mortality and economic losses. Recently, there has been a spike in the incidence of a viral disease caused by Tilapia Parvovirus (TiPV) inflicts irreparable damage, and large-scale fish kills in the farmed tilapia species. We investigated a case of disease outbreak and severe mortality in cage and wetland farms of tilapia in West Bengal and Odisha, India. The symptomatic fish showed clinical signs, including hemorrhage, discoloration, ulcer, and redness in the body surfaces. Further analysis revealed that Tilapia Parvovirus was associated (validated by PCR, phylogenetic analysis, and cell line assay) with the infection and mortality of tilapia. The virus was detected in gill, heart, spleen, liver, and kidney samples collected from apparently healthy (asymptomatic) and symptomatic tilapia samples from cage and wetland farms. At the same time, negative results were found in the brain and skin tissue samples. The histological analysis revealed that TiPV induces severe damage invariably in almost all studied tissue, including the liver, kidney, spleen, gill, heart, and brain of tilapia samples. The viral quantification analysis showed that the viral genome was higher in the liver, spleen, and heart than in the tilapia samples' gill, kidney, or brain tissue. Furthermore, the study indicated that TiPV infection has a significant effect on the health of tilapia. The tilapia exhibited an immune reactivity toward TiPV infection (upregulation of chemokine receptors, CRs and interleukin 1β, IL-1β), the majority of the studied immune genes (interleukin 8, IL-8; Toll-like receptors 7, TLR7; tumour necrosis factor α, TNF-α; major histocompatibility complex II, MHC II and nuclear factor kappa B, NF-kB) were significantly downregulated in the kidney, spleen and liver tissue samples of symptomatic tilapia. Further, the in vivo challenge assay confirms that the isolated TiPV is a novel parvovirus pathogen that causes massive mortality in tilapia. The lessons learned from the first cellular and molecular description associated with TiPV epidemiology from wetland and cage farms of tilapia could be critical to developing the current state of the tilapia farming industry. Additionally, a holistic approach is needed to develop management measures to control the virulence and risk factors of TiPV.

Astragalus polysaccharide treatment relieves cerebral ischemia‒reperfusion injury by promoting M2 polarization of microglia by enhancing O-GlcNAcylation.

Cerebral ischemia‒reperfusion (I/R) injury seriously threatens the lives of patients. Astragalus polysaccharide (APS) is the main active ingredient of Astragalus membranaceus and has a wide range of pharmacological activities. Here, we aimed to explore the impacts of APS on cerebral I/R injury and its specific mechanisms. We established a cerebral I/R injury model using middle cerebral artery occlusion (MCAO)-treated rats and oxygen glucose deprivation/reoxygenation (OGD/R)-treated BV2 cells. The interleukin 1β (IL-1β), interleukin 6 (IL-6) and interleukin (IL-10) levels were determined using corresponding ELISA kits and RT‒qPCR. The levels of M1 microglial markers (INOS and CD16) and M2 microglial markers (Arg-1 and CD206) were measured by RT‒qPCR. The O-linked N-acetylglucosamine modification (O-GlcNAcylation), O-GlcNAc transfer (OGT) and O-GlcNAc glycosidase (OGA) protein levels were measured by Western blot.Our results showed that APS treatment decreased IL-1β (179.72 ± 9.08 vs. 81.33 ± 6.30) and IL-6 (445.56 ± 33.09 vs. 234.75 ± 27.62) levels and increased IL-10 (41.95 ± 4.18 vs. 86.40 ± 7.16) levels in OGD/R-treated BV2 cells (p < 0.001). In addition, APS promoted the M2 polarization of OGD/R-treated BV2 cells, manifested by an increase in Arg-1 (0.43 ± 0.04 vs. 0.76 ± 0.03) and CD206 (0.36 ± 0.03 vs. 0.65 ± 0.06) and a decrease in INOS (2.84 ± 0.39 vs. 1.56 ± 0.19) and CD16 (4.04 ± 0.36 vs. 1.88 ± 0.09) in OGD/R-treated BV2 cells (p < 0.001). Additionally, APS treatment increased the O-GlcNAcylation and OGT levels in OGD/R-treated BV2 cells, while OGT knockdown reversed the effect of APS in OGD/R-treated BV2 cells and MCAO-treated rats (p < 0.05).Our study demonstrated that APS alleviated cerebral I/R injury by promoting the M2 polarization of microglia by enhancing OGT-mediated O-GlcNAcylation.

Association of Pro-inflammatory Cytokines with Gastric Cancer Risk: A Case-Cohort Study.

This study aimed to assess the association between inflammatory cytokines and the risk of gastric cancer (GC). We conducted a case-cohort study using Korean National Cancer Center Community (KNCCC) cohort data to investigate the associations between pro-inflammatory, anti-inflammatory cytokines, inflammatory mediators, and GC risk in the Korean general population (GC cases: n=159, subcohort: n=822). Serum levels of inflammatory cytokines were measured using Quantikine® ELISA and analyzed using a Cox proportional hazards regression model. Compared to those with the lowest serum interleukin 6 (IL-6) levels, the risk of GC significantly increased in the second (HR: 3.48 [1.73-6.99]), third (HR: 3.74 [1.91-7.29], and fourth quartiles (HR: 3.79 [1.93-7.48]). Elevated levels of interleukin 1β (IL-1β) (HR: 1.57 [1.12-2.21]) and interferon gamma (IFN-γ) (HR: 2.49 [1.73-3.58]) were also associated with an increased risk of GC. The findings of this study indicate associations between pro-inflammatory cytokines (IL-6, IL-1β, and IFN-γ) and the risk of GC, suggesting that regulating these cytokine levels may aid in GC prevention.

Natural AI-based drug designing by modification of ascorbic acid and curcumin to combat buprofezin toxicity by using molecular dynamics study

Buprofezin, a widely employed insecticide in agricultural practices, has elicited significant apprehension due to its prospective deleterious effects on non-target organisms and ecological systems. Its enduring presence in terrestrial and aquatic environments presents potential hazards to human health and biodiversity, thereby necessitating the investigation of safer alternatives or strategies for mitigation. The research focuses on five principal receptors: CAT (Catalase), IL-1B (Interleukin-1 Beta), IL-6 (Interleukin-6), TNF-alpha (Tumor Necrosis Factor-alpha), and SOD (Superoxide Dismutase). These receptors are integral to the processes of inflammation, oxidative stress, and immune responses, rendering them critical for comprehending the biochemical pathways affected by toxic substances and the potential for protective interventions. The investigation employed WADDAICA (Webserver-Aided Drug Design by Artificial Intelligence) to formulate AI-driven pharmaceuticals, complemented by ADME (Absorption, Distribution, Metabolism, Excretion) evaluations, Molecular Dynamics (MD) simulations, as well as MMGBSA and MMPBSA methodologies to examine the stability and interactions of the compounds with the designated receptors. Docking experiments disclosed that the interaction of CAT with the ascorbic acid AI-derived drug demonstrated a binding energy of -7.1 kcal/mol, signifying a robust interaction, while the complex of IL-1B with the curcumin AI-derived drug exhibited a binding energy of -7.3 kcal/mol. The ADME analysis revealed favorable gastrointestinal absorption and aqueous solubility for both compounds. Furthermore, the drug-likeness metrics were deemed satisfactory, with no breaches of Lipinski’s rule of five, suggesting promising potential for subsequent advancement as therapeutic agents.

Unleashing the power of golden berry leaves to counteract cyclophosphamide's toll with antioxidant, anti-inflammatory, anti-apoptotic, and neurotransmitter boosting effects

Ethnopharmacological relevanceGolden berries (Physalis peruviana) are esteemed for their healing properties and widespread use in traditional medicine, particularly for their neuroprotective benefits. Aim of the studyThis work aims to evaluate the neuroprotective effect of golden berry total leaf extract cultivated in Egypt (TLE) against cyclophosphamide (CP)-induced neurotoxicity and to identify the chemical composition of different organs of P. peruviana from both Egypt and USA. Material and methodsMetabolite profiling of TLE was conducted using ultra-high-performance liquid chromatography combined with quadrupole time-of-flight tandem mass spectrometry (UHPLC-QTOF-MS/MS). In the animal model experiment, CP (100 mg/kg, i.p.) was administered once weekly for four weeks to induce neurocognitive dysfunction. Concurrently, TLE (500 mg/kg, orally) was administered twice weekly throughout the four weeks to evaluate its effectiveness in alleviating CP-induced neuronal deficits. Behavioral assessments, Morris water maze and passive avoidance tests, were conducted, followed by, histological evaluations of brain tissue samples. Additionally, biochemical analyses were performed on hippocampal tissue samples, examining the following markers, acetylcholinesterase activity (AChE), malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT) activity, nuclear factor kappa B (p-NF-κB p65) (Ser536), Interleukin 1β (IL-1β), Interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), B-cell lymphoma 2 (Bcl-2), and Bax (Bcl-2-associated X) levels. ResultsTLE significantly preserved hippocampal neurons and improved cognitive performance in behavioral tests. TLE achieved these beneficial effects by suppressing AChE activity, diminishing the oxidative stress and restoring redox balance via inhibiting p-NFκB/IL-1β,/TNFα/IL-6 cascades. Leaf extract revealed the highest total phenolic content (TPC) (2.7 ± 6.41 mg GAE/g extract) and total flavonoid content (TFC) (0.37 ± 1.19 mg QE/g) and the strongest antioxidant effects in Ferric Reducing Antioxidant Power (FRAP) and 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays with IC50 values of 21.13 ± 1.48 and 18.19 ± 1.29 μg/mL, respectively. UHPLC–QTOF-MS/MS analysis resulted in the tentative identification of 20 metabolites including phenolic acids, flavonoids, hydroxycinnamic acid amides, and alkyl resorcinols. ConclusionsFindings verify for the first time the neuroprotective potential of golden berry leaf, currently discarded as agricultural waste, and highlight its multifaceted mechanism of neuroprotection in CP-induced neurotoxicity, suggesting its suitability as a promising therapeutic agent for neurotoxicity management.

Sumac liposomes/mesenchymal stem cells fight methotrexate-induced nephrotoxicity in rats via regulating Nrf-2/Keap-1/HO-1 and apoptotic signaling pathways.

Methotrexate (MTX) is commonly employed in cancer treatment, but its clinical use is restricted due to the MTX-associated renal injury. This study investigates the combined potential of Rhus coriaria (sumac) and bone marrow mesenchymal stem cells (BMMSCs) against MTX-induced nephrotoxicity in rats. The high-resolution-liquid chromatography-mass spectrometry (HR-LC-MS) of sumac extract tentatively identified 22 phytochemicals, mostly flavonoids, anthocyanins, and steroids. Preparation of sumac liposomes attained a suitable particle size of 3041.33 ± 339.42 nm, a polydispersity index of 0.208 ± 0.086, and an encapsulation efficiency of 84.92 ± 3.47%. Rat BMMSCs were injected into the tail vein of the experimental rats (0.5 × 106 cells, intravenous [iv]) of seven treated groups. The experimental design relies on either pre- or posttreatment of rats with intraperitoneal (IP) sumac liposomes (SL) (200 mg/kg, daily with a dose of MTX (300 µg/kg/14 days). The histopathological examination and serum analysis of creatinine and urea revealed good results, besides regulating levels of oxidative stress and inflammatory markers. Additionally, a significant decrease in the gene expression levels of B-Cell Lymphoma 2 (Bcl-2) and caspases-3 and -9, a remarkable increase in the Bcl-2 Associated X-Protein (Bax), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme-oxygenase 1 expression, and a downregulation of Kelch-like ECH-associated protein 1 (Keap1). Collectively, the coadministration of SL with BMMSCs might be a potent therapeutic strategy for attenuation of MTX-induced renal damage. The network pharmacology analysis identified the involved key hub genes as KEAP1, Nrf2, HMOX1, mitogen-activated protein kinase (MAPK1), nuclear factor-kappa B (NF-KB), interleukin-1 beta (IL-1B), and caspase-3. The docking results revealed strong binding affinities of 7-O-methyl-cyanidin-3-O-(2″-galloyl)-galactoside with Keap1 and amentoflavone with MAPK. These insights pave the way for future experimental validation and therapeutic development of sumac-based phytoconstituents against MTX-induced nephrotoxicity.