Pro-inflammatory Cytokines IL-6 Research Articles

Investigation of Oxidative Stress Parameters and Pro-Inflammatory Cytokines in a Neuropathy Model Created with Taraxacum Officinale L. Leaf Extract and Cisplatin

The aim of this study was to investigate the effect of Taraxacum officinale leaf extract, a plant known for its potent antioxidant and anti-inflammatory properties, on cisplatin-induced neurotoxicity. Cancer treatment has demonstrated platinum drugs, particularly cisplatin, as among the most effective treatments. However, the drug comes with serious side effects. The use of cisplatin is limited due to its cytotoxic effects, potentially preventing patients from benefiting optimally from anticancer agents. Taraxacum officinale has been used for various diseases for years, observed clinically in conditions such as dyspepsia, liver, gallbladder, and urinary disorders. Nowadays, Taraxacum officinale has entered our lives in various forms as a dietary supplement. However, this plant possesses many bioactivities, particularly potent anti-inflammatory, antioxidant, and hepatoprotective properties.In this study, chronic cisplatin administration was used to induce a peripheral neuropathy model, administered intraperitoneally (i.p) once a week for 5 weeks at a dose of 3 mg/kg. Taraxacum officinale leaf extract was administered intragastrically once daily at a dose of 500mg/kg for the same duration to determine its potential effects on cisplatin neuropathy. After drug administration, motor performance was evaluated using the rotarod test, while sensory transmission status was assessed using tail withdrawal and hot/cold plate tests. Oxidative stress parameters and proinflammatory cytokine markers were analyzed biochemically. In animals exposed to cisplatin, thermal hypoalgesia and cold hypoalgesia were observed (p<0.001), motor coordination balance was prolonged with the rotarod test (p<0.001), and tail withdrawal time was extended (p<0.001). Biochemically, oxidative stress parameters TOS (p<0.05), OSI (p<0.05), and MDA (p<0.05) levels significantly increased compared to the cisplatin control group. TAS levels provided a statistically significant increase compared to the cisplatin-administered group (p<0.05). Proinflammatory cytokine markers TNF-α (p<0.05), IL-6 (p<0.001), and NFKB (p<0.05) levels were found to be higher compared to the cisplatin control group. It was determined that Taraxacum officinale improved these side effects induced by cisplatin both behaviorally and biochemically. In conclusion, Taraxacum officinale leaf extract is a plant with potent antioxidant and anti-inflammatory activity.

Changes in Innate Immunity and Microbiome in Different Aging Phenotypes.

The indicators of innate immunity and the composition of the microbiome in the nasopharyngeal mucosa in centenarians with different aging phenotypes were analyzed. A significant increase in the expression of pattern-recognizing receptor genes (TLR2, TLR4, and NLRP3) and proinflammatory cytokines (IL1B, IL18) was shown in the group of centenarians with pathological aging phenotype. In centenarians with successful aging phenotype, increased diversity of the microbiome composition was observed. At the same time, a moderate inverse correlation was found between an increase in the growth of the commensal bacterium Streptococcus salivarius and a decrease in the expression of proinflammatory cytokine genes IL1B and IL18. These findings can serve as biomarkers for the timely identification of the phenotype of aging in senile and elderly people.

Cucurbitacin IIb alleviates colitis via regulating gut microbial composition and metabolites

Cucurbitacin IIb, a member of the triterpenoid family, exerts beneficial effects on intestinal diseases, including enteritis and bacillary dysentery. However, its effects and mechanisms of action on colitis have not yet been explored. In this study, we used a mouse model of dextran sulfate sodium (DSS)-induced colitis and explored the effects of cucurbitacin IIb on colitis symptoms, inflammatory responses, microbiota, and metabolite profiles. The results showed that cucurbitacin IIb alleviated colitis symptoms including body weight loss, an increase in the disease activity index, and elevated levels of myeloperoxidase and eosinophil peroxidase content. Additionally, it ameliorated intestinal morphology impairment, reduced the phosphorylation of NFκB protein, and mitigated accumulation of pro-inflammatory cytokines IL-6 and IL-1β. Furthermore, cucurbitacin IIb alleviated alterations in gut microbial composition and metabolites in DSS-treated mice. However, antibiotic treatment diminishes the beneficial effects of cucurbitacin IIb on colitis. We further found that transplantation of fresh feces or heat-inactivated feces from mice treated with cucurbitacin IIb to DSS-treated mice alleviated colitis, similar to the effects of cucurbitacin IIb. Collectively, our results suggest that cucurbitacin IIb exerted anti-inflammatory effects in colitis by regulating the microbiota composition and metabolites, thereby alleviating colitis symptoms.

Lactobacillus delbrueckii alleviates lipopolysaccharide-induced muscle inflammation and atrophy in weaned piglets associated with inhibition of endoplasmic reticulum stress and protein degradation.

Pro-inflammatory cytokines in muscle play a pivotal role in physiological responses and in the pathophysiology of inflammatory disease and muscle atrophy. Lactobacillus delbrueckii (LD), as a kind of probiotics, has inhibitory effects on pro-inflammatory cytokines associated with various inflammatory diseases. This study was conducted to explore the effect of dietary LD on the lipopolysaccharide (LPS)-induced muscle inflammation and atrophy in piglets and to elucidate the underlying mechanism. A total of 36 weaned piglets (Duroc × Landrace × Large Yorkshire) were allotted into three groups with six replicates (pens) of two piglets: (1) Nonchallenged control; (2) LPS-challenged (LPS); (3) 0.2% LD diet and LPS-challenged (LD+LPS). On d 29, the piglets were injected intraperitoneally with LPS or sterilized saline, respectively. All piglets were slaughtered at 4 h after LPS or saline injection, the blood and muscle samples were collected for further analysis. Our results showed that dietary supplementation of LD significantly attenuated LPS-induced production of pro-inflammatory cytokines IL-6 and TNF-α in both serum and muscle of the piglets. Concomitantly, pretreating the piglets with LD also clearly inhibited LPS-induced nuclear translocation of NF-κB p65 subunits in the muscle, which correlated with the anti-inflammatory effects of LD on the muscle of piglets. Meanwhile, LPS-induced muscle atrophy, indicated by a higher expression of muscle atrophy F-box, muscle RING finger protein (MuRF1), forkhead box O 1, and autophagy-related protein 5 (ATG5) at the transcriptional level, whereas pretreatment with LD led to inhibition of these upregulations, particularly genes for MuRF1 and ATG5. Moreover, LPS-induced mRNA expression of endoplasmic reticulum stress markers, such as eukaryotic translational initiation factor 2α (eIF-2α) was suppressed by pretreatment with LD, which was accompanied by a decrease in the protein expression levels of IRE1α and GRP78. Additionally, LD significantly prevented muscle cell apoptotic death induced by LPS. Taken together, our data indicate that the anti-inflammatory effect of LD supply on muscle atrophy of piglets could be likely regulated by inhibiting the secretion of pro-inflammatory cytokines through the inactivation of the ER stress/NF-κB singling pathway, along with the reduction in protein degradation.

Health-Promoting Properties of Pectin-Polyphenol Complex Extracted from Olive Oil By-Product Alperujo: Antioxidant, Antiproliferative, and Anti-Inflammatory Activities.

This research explores the health-promoting properties of the pectin-polyphenol complex extracted from alperujo, a by-product of olive oil production. This study investigates the chemical composition and antioxidant activity of the extracts, revealing their high antioxidant activity in vitro. Cell viability assays conducted on colon carcinoma cells (Caco-2) demonstrate the inhibitory effect of the extracts on cell proliferation. However, the extracts do not affect the viability of differentiated Caco-2 cells, suggesting a selective antiproliferative action. Additionally, the extracts reduce intracellular reactive oxygen species (ROS) and nitrite (NO) production in LPS-stimulated murine peritoneal macrophages. Furthermore, the extracts exhibit anti-inflammatory effects by downregulating the secretion of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 in these macrophages. These findings highlight the potential of pectin-polyphenol complexes as functional ingredients with significant health benefits, demonstrating antioxidant, antiproliferative, and anti-inflammatory properties.

Metformin Alleviates Inflammation and Induces Mitophagy in Human Retinal Pigment Epithelium Cells Suffering from Mitochondrial Damage.

Mitochondrial malfunction, excessive production of reactive oxygen species (ROS), deficient autophagy/mitophagy, and chronic inflammation are hallmarks of age-related macular degeneration (AMD). Metformin has been shown to activate mitophagy, alleviate inflammation, and lower the odds of developing AMD. Here, we explored the ability of metformin to activate mitophagy and alleviate inflammation in retinal pigment epithelium (RPE) cells. Human ARPE-19 cells were pre-treated with metformin for 1 h prior to exposure to antimycin A (10 µM), which induced mitochondrial damage. Cell viability, ROS production, and inflammatory cytokine production were measured, while autophagy/mitophagy proteins were studied using Western blotting and immunocytochemistry. Metformin pre-treatment reduced the levels of proinflammatory cytokines IL-6 and IL-8 to 42% and 65% compared to ARPE-19 cells exposed to antimycin A alone. Metformin reduced the accumulation of the autophagy substrate SQSTM1/p62 (43.9%) and the levels of LC3 I and II (51.6% and 48.6%, respectively) after antimycin A exposure. Metformin also increased the colocalization of LC3 with TOM20 1.5-fold, suggesting active mitophagy. Antimycin A exposure increased the production of mitochondrial ROS (226%), which was reduced by the metformin pre-treatment (84.5%). Collectively, metformin showed anti-inflammatory and antioxidative potential with mitophagy induction in human RPE cells suffering from mitochondrial damage.

Schizonepeta tenuifolia Briq-Saposhnikovia divaricata decoction alleviates atopic dermatitis via downregulating macrophage TRPV1.

Schizonepeta tenuifolia -Saposhnikovia divaricata (Jingjie-Fangfeng, JF) has been used for years to treat allergic inflammatory skin diseases like atopic dermatitis, but the specific effects and mechanisms of JF are still unclear. We aim to investigate the therapeutic effect and mechanism of JF in MC903-induced atopic dermatitis-like model. JF decoction was subjected to rigorous HPLC and GC analysis. The JF decoction was then freshly prepared and administered to MC903-induced atopic dermatitis -like mice models to investigate its therapeutic effects. Our evaluation focused on several markers of inflammation including the TEWL index, ear thickness, swelling, and specific inflammation indicators such as TSLP, IL33, IgE, and immune cell presence at the lesion sites. We measured Transient Receptor Potential Vanilloid 1 (TRPV1) expression levels through immunofluorescent staining in skin tissue from both atopic dermatitis patients and the MC903-treated mice. Furthermore, TRPV1 expression and macrophage activation markers were measured in LPS/IFN-γ-stimulated Raw264.7 and THP-1 cell models in vitro. Additionally, we developed cell lines that overexpress TRPV1 and investigated how JF treatment affects NF-κB p65 phosphorylation in these cells to understand better the role of TRPV1 in atopic dermatitis. The JF decoction met the standards outlined in the Chinese pharmacopeia. The JF decoction significantly alleviated inflammatory skin symptoms and helped restore skin barrier function. Additionally, it reduced the levels of IgE and pro-inflammatory cytokines TSLP, IL-33, and IL-4. There was also a noticeable decrease in mast cell infiltration and degranulation. Notably, JF decoction reduced infiltrated macrophages with limited affection on T cell infiltration. It also decreased F4/80+/TRPV1+ cells in atopic dermatitis mice and TRPV1 expression in LPS/IFNγ-stimulated microphages. Additionally, we observed that CD68+/TRPV1+ cells increased in human atopic dermatitis tissue. Further studies showed that JF water extract (JF-WE) suppressed TRPV1 expression in macrophages, potentially by affecting NF-κB p65 phosphorylation rather than the JAK-STAT6 pathway. This study offers initial evidence of the effectiveness of JF-WE in suppressing inflammation in atopic dermatitis. The therapeutic effect might stems from its ability to downregulate TRPV1 expression and subsequent NF-κB p65 phosphorylation in macrophages.

Maternal negative affect in pregnancy predicts cytokine levels which in turn predict birth outcomes – A prospective longitudinal study in a low-risk population

BackgroundStress and negative mood in pregnancy have been linked to less favorable birth outcomes, but the mechanisms underlying this effect remain largely unknown. We examined associations between emotions in pregnancy, pro- and anti-inflammatory cytokines (IFN-γ, IL-6, IL-8, IL-10, IL-12, IL-17, MCP-1, MIP-1β, TNF-α) and birth outcomes (gestational age at birth and birth weight) in a low-risk sample. MethodsAt each trimester of pregnancy, participants (N = 74) completed the Positive and Negative Affect Schedule, Perceived Stress Scale, Edinburgh Postnatal Depression Scale, and State-Trait Anxiety Inventory. They provided blood samples in the third trimester. Multivariate regression with a reduction of dimensionality (orthogonal projection to latent structures) was used to assess associations between maternal emotions, cytokine levels, and birth outcomes. ResultsWe found significant positive associations between negative mood (depressive symptoms in the second and third trimesters and negative affect in the third trimester) and anti-inflammatory cytokine IL-10 levels, and negative associations between maternal distress in the second and third trimesters and pro-/anti-inflammatory cytokine ratios (IFN-γ/IL-10, TNF-α/IL-10 and IL-6/IL-10). Higher levels of pro-inflammatory cytokines IFN-γ, IL-12, IL-17, and TNF-α were associated with younger gestational age at birth and lower birth weight. LimitationsWe did not control for relevant factors such as social support, health-related behaviors, or cortisol levels. ConclusionsNegative mood in mid- and late pregnancy may shift cytokine balance toward the anti-inflammatory cytokine dominance. Our results provide further evidence for the negative association between pro-inflammatory cytokines in late pregnancy and gestational age at birth/birth weight, which we observed even in a low-risk population.

Exploration of Potential Anti-Inflammatory Cum Anti-Rheumatoid-Arthritis Phyto-Molecule Through Integrated Green Approach: Network Pharmacology, Molecular Docking, Molecular Dynamics, In-Vitro and Ex-Vivo Study.

Rheumatoid arthritis (RA) and associated inflammatory complications are the most prevalent illnesses and can turn into fatal conditions if left untreated. Allopathic medicine is not satisfactory for curing RA. Scientific literature reports reveal that several phyto-compounds viz. flavonoids, saponins, and terpenoids, can heal joints and organs from auto-inflammatory rheumatoid arthritis and pain. Gene ontology, gene network analysis, molecular clustering, and literature review were used to optimise RA-specific highly expressed genes. In-silico molecular docking was performed to short-out potential phytomolecules (Neohesperidin dihydrochalcone (NHDC)) from 1000 datasets-library against RA and validate using MD simulation running at 100 ns. In-vitro anti-inflammatory assays of NHDC inhibited egg-albumin denaturation, IC50 of 47.739±0.51 μg/ml. The ex-vivo MTT assay with NHDC rendered 67.209 % inhibition at 100 μM against fd-FLS-cells. NHDC downregulated pro-inflammatory cytokine IL-17 A production by 61.11 % and 50 % at 300 and 200 μM, respectively. Thus, this Studies recommend that NHDC may be highlighted as a novel multi-target PADI4 and JAK3 inhibitor with better efficacy and minimal toxicity in RA warranted to In-Vivo and clinical investigation. The current findings have uncovered remarkable genes and signalling pathways linked to RA, which could enhance our existing comprehension of the molecular mechanisms that drive its development and progression.

Tocilizumab Prophylaxis Following Axicabtagene Ciloleucel in Relapsed or Refractory Large B-Cell Lymphoma

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Most patients treated with axi-cel experience cytokine release syndrome (CRS) and/or adverse neurologic events (NEs). To explore potential approaches for reducing CAR T-cell-related toxicities with axi-cel, several safety expansion cohorts were added to the pivotal ZUMA-1 trial. ZUMA-1 Cohort 3 was an exploratory safety cohort that investigated the use of the IL-6 receptor-blocking antibody tocilizumab and anticonvulsant levetiracetam as prophylaxis against CRS and NEs in patients treated with axi-cel. Patients with R/R LBCL were enrolled in Cohort 3 and received conditioning chemotherapy on d -5 through -3 followed by a single infusion of axi-cel (2 × 106 cells/kg) on d 0. Prophylactic tocilizumab (8 mg/kg) was administered 48 h after axi-cel infusion. Primary endpoints were incidence and severity of CRS and NEs. Key secondary endpoints included the incidence of adverse events, objective response rate (ORR), duration of response, progression-free survival, overall survival (OS), and biomarker analyses (eg, circulating CAR T cells, cytokines, chemokines). Forty-two patients were enrolled in Cohort 3, 38 of whom received axi-cel. In the 24-month analysis, any-grade CRS and NEs occurred in 92% and 87% of patients, and Grade ≥3 CRS and NEs occurred in 3% and 42% of patients, respectively. One Grade 5 NE (cerebral edema) occurred. With 24-mo minimum follow-up, the ORR was 63%, and 39.5% of patients had ongoing response. With 48-month follow-up, median OS was 34.8 mo (95% CI, 5.4-not estimable). CAR T-cell expansion in ZUMA-1 Cohort 3 was comparable with pivotal Cohorts 1 and 2. Consistent with tocilizumab-mediated inhibition of IL-6R, serum IL-6 levels were increased relative to Cohorts 1 and 2. Grade ≥3 NEs were associated with elevated IL-6 levels, proinflammatory cytokines, and myeloid cells in the cerebrospinal fluid. Based on these findings, prophylactic tocilizumab is not recommended to prevent CAR T-cell-related adverse events, and beneficial effects of prophylactic levetiracetam remain uncertain in patients with R/R LBCL.

Canagliflozin Mitigates Acute Kidney Injury Secondary to Resuscitative Endovascular Balloon Occlusion of the Aorta in a Porcine Model of Hemorrhagic Shock.

We investigated the potential of acute canagliflozin administration to mitigate acute kidney injury (AKI) and attenuate deleterious pro-inflammatory cytokine release in a clinically relevant swine model of severe renal ischemia reperfusion injury (IRI) induced by hemorrhage and aortic occlusion. Long-term canagliflozin use attenuates renal function decline and reduces AKI in diabetes mellitus and heart failure patients. Whilst several reports indicate prophylactic SGLT2 inhibition prevents AKI in IRI, the efficacy of acute administration on IRI and inflammation is not known. Female swine (n=16) underwent controlled hemorrhage of 25% blood volume, followed by 90 min of aortic occlusion at the level of the renal ostia (via Resuscitative Endovascular Balloon Occlusion of the Aorta). A single 300mg dose of oral canagliflozin or vehicle (saline) was delivered 5 mins into aortic occlusion. Hemodynamic monitoring, markers of renal function (serum creatinine, blood urea nitrogen, proteinuria and urinary neutrophil gelatinase-associated lipocalin) and serum cytokine concentrations (including interleukins: IL-1RA, IL-6, IL-8, IL-10, IL-18; and Tumor necrosis factor alpha) were analyzed after IRI, and during a 6h critical care phase. Compared to controls, animals receiving canagliflozin had less severe AKI, improved creatinine clearance, reduced proteinuria, and significantly lower tubular damage as evidenced by histopathology and urinary NGAL. Furthermore, the pro-inflammatory cytokine IL-6 was markedly attenuated without reduction in anti-inflammatory cytokines (IL-1RA and IL-10). A single dose of canagliflozin administered shortly into ischemic insult mitigates AKI and attenuates harmful pro-inflammatory cytokine release following trauma or surgery. These findings suggest a potential novel therapeutic role for canagliflozin in mitigating the effects of renal IRI worthy of further investigation.

Polychlorinated Biphenyls (PCBS)-induced oxidative stress and inflammation in human thyrocytes: involvement of AhR and NRF-2/HO-1 pathway.

In this in vitro study, we investigated the effects of polychlorinated biphenyls (PCBs) on human thyrocytes, with a focus on the involvement of AhR, a key player in xenobiotic response, and the anti-oxidant Nrf-2/HO-1 pathway. Primary cultured thyrocytes were exposed to the dioxin-like congeners PCB118 and PCB126 at 2.5 and 5 µM concentrations. mRNA expression was assessed by real-time PCR, and protein expression by Western Blot and ELISA, while protein quantification was assessed by densitometric analysis. In cultured thyrocytes, PCB118 and PCB126 induced a significant (P < 0.01) increase of mRNA and protein levels of the pro-inflammatory cytokines IL-1beta and IL-6, while reducing those of thyroglobulin (TG) and NIS (p < 0.05), indicating down-regulation of these thyroid-specific genes in PCB-induced inflammation. ROS production also increased (p < 0.001). mRNA levels of AhR and the downstream molecules cytochrome P4501A, Nrf-2/HO-1 increased (p < 0.001), as well as related protein levels (p < 0.01), suggesting the activation of AhR and Nrf-2 pathways in response to PCBs exposure. AhR silencing decreased AhR-related gene expression and restored NIS and TG expression, while reducing inflammatory cytokines and oxidative stress markers (p < 0.05). Dioxin-like PCBs (PCB118 and PCB126) may promote inflammation and oxidative stress in thyrocytes, impairing the expression of genes that are key players of thyroid function. These effects can be partially attributed to the activation of the AhR and Nrf-2 pathways. These data may contribute to explain the mechanisms underlying thyroid toxicity of PCBs, highlighting the potential role of these pollutants as a trigger of autoimmune thyroid inflammation and damage.

Effect of Dexmedetomidine in Video-Assisted Thoracoscopic Surgery: A Randomized Controlled Study

Background: One-lung ventilation is used to improve surgical visualization and facilitate thoracoscopic manipulations; however, it induces ventilation/perfusion mismatch, exacerbating the inflammatory response that causes hypoxemia in the perioperative period. Opioid analgesics are the main analgesic drugs used during video-assisted thoracoscopic surgery (VATS), but their use is associated with adverse effects and higher risk of respiratory complications. Corrective measures to eliminate hypoxemia, reduce the inflammatory response, control pain, and minimize opioid-induced adverse effects are crucial in thoracic surgery.Objective: To study the efficacy of dexmedetomidine in reducing lung damage and postoperative complications after VATS.Materials and methods: We examined 100 patients who underwent lobectomy via a thoracoscopic approach. The patients were grouped based on anesthetic management: group 1 (n = 50) with intraoperative dexmedetomidine and group 2 (n = 50) without it. We determined the level of pro-inflammatory cytokines IL-6, IL-8, and TNF and calculated PaO2/FiO2 and A-aDO2. We also assessed the postoperative pain intensity, need for trimeperidin promedol and tramadol, and incidence of postoperative complications.Results: During one-lung ventilation, patients from group 1 had higher PaO2/FiO2 values (P = .025). The A-aDO2 value was higher in group 2 (P = .006). After surgery, we found differences in the content of TNF and IL-8 (P &lt; .001). Twenty-four hours after surgery, we recorded a more significant prevalence of the studied cytokines in group 2 (P &lt; .001). There were no significant differences in the pain dynamics on the first postoperative day (P &gt; .05). Opioid analgesics were less needed in group 1 than in group 2 (P &lt; .001). The incidence of postoperative complications did not differ significantly.Conclusions: Dexmedetomidine in thoracic surgery improves the oxygenation and reduces the percentage of intrapulmonary shunting by inhibiting the release of pro-inflammatory cytokines. In the postoperative period, dexmedetomidine reduces the need for opioid analgesics, but does not affect the pain level or incidence of complications.

Response of bovine endometrium to interferon tau in the presence of lipopolysaccharide

We recently demonstrated that conceptus-derived interferon tau (IFNT), responsible for maternal recognition in cattle, acts on the uterus in a dose- and time-dependent manner by upregulating key interferon-stimulated genes (ISGs) in the endometrium. In high producing dairy cows, postpartum uterine infection is a major factor influencing fertility and pregnancy outcome. Lipopolysaccharide (LPS), an endotoxin of Gram-negative bacteria such as Escherichia coli, generates an altered uterine environment by inducing excessive inflammation at the maternal-conceptus interface. Thus, we aimed to investigate whether the endometrial response to IFNT is altered in the presence of LPS. Endometrial explants were isolated from uteri collected at a local abattoir from Holstein Friesian cows (n = 8) during the mid-luteal stage of the estrous cycle, and cultured in RPMI medium for 24 h in 5 % CO2 in humidified air without (control), or with IFNT (100 ng/mL), a single Day 15 conceptus, LPS (1 μg/mL), both IFNT and LPS, or both a Day 15 conceptus and LPS. Incubation with IFNT and a Day 15 conceptus up-regulated (P < 0.05) well-known classical ISGs (ISG15, OAS1, MX1 and MX2) as well as other candidate ISGs (CMPK2, IFI35, TRIM38 and TNFSF10) and down-regulated expression of IL1B in endometrial explants. Incubation with LPS increased (P < 0.05) abundance of NFKB1 (a key transcription factor involved in inflammatory and immune response), TNFA, IL1B and IL6 (pro-inflammatory cytokines), IL10 (anti-inflammatory cytokine), IL8, CXCL1, CXCL3 and CCL2 (chemokines), and, to a lesser extent, classical ISGs in endometrial explants. However, LPS did not alter endometrial response to IFNT, irrespective of IFNT concentration (1, 10 or 100 ng/mL). Results suggest that the expression of ISGs, up-regulated by conceptus-derived IFNT, is not altered in the endometrium in the presence of LPS; however, the increased expression of inflammation-related genes induced by LPS indicate an altered endometrial immune response that may be associated with compromised pregnancy establishment or pregnancy failure.

Pretreatment with oleuropein protects the neonatal brain from hypoxia-ischemia by inhibiting apoptosis and neuroinflammation.

Hypoxic-ischemic (HI) encephalopathy is a cerebrovascular injury caused by oxygen deprivation to the brain and remains a major cause of neonatal mortality and morbidity worldwide. Therapeutic hypothermia is the current standard of care but it does not provide complete neuroprotection. Our aim was to investigate the neuroprotective effect of oleuropein (Ole) in a neonatal (seven-day-old) mouse model of HI. Ole, a secoiridoid found in olive leaves, has previously shown to reduce damage against cerebral and other ischemia/reperfusion injuries. Here, we administered Ole as a pretreatment prior to HI induction at 20 or 100 mg/kg. A week after HI, Ole significantly reduced the infarct area and the histological damage as well as white matter injury, by preserving myelination, microglial activation and the astroglial reactive response. Twenty-four hours after HI, Ole reduced the overexpression of caspase-3 and the proinflammatory cytokines IL-6 and TNF-α. Moreover, using UPLC-MS/MS we found that maternal supplementation with Ole during pregnancy and/or lactation led to the accumulation of its metabolite hydroxytyrosol in the brains of the offspring. Overall, our results indicate that pretreatment with Ole confers neuroprotection and can prevent HI-induced brain damage by modulating apoptosis and neuroinflammation.

GDNF's Role in Mitigating Intestinal Reactive Gliosis and Inflammation to Improve Constipation and Depressive Behavior in Rats with Parkinson's disease.

Constipation is a common symptom in patients with Parkinson's disease (PD) and is often associated with depression. Enteric glial cells (EGCs) are crucial for regulating intestinal inflammation and colon motility, and their activation can lead to the death of intestinal neurons. Glial cell line-derived neurotrophic factor (GDNF) has been recognized for its neuroprotective properties in various neurological disorders, including PD. This study explores the potential of GDNF in alleviating intestinal reactive gliosis and inflammation, thereby improving constipation and depressive behavior in a rat model of PD.A PD model was established via unilateral stereotaxic injection of 6-hydroxydopamine (6-OHDA). Five weeks post-injury, AAV5-GDNF (2 ~ 5 × 10^11) was intraperitoneally injected into experimental and control rats. Fecal moisture percentage (FMP) and colonic propulsion rate (CPPR) were used to evaluate colon motility. Colon-related inflammation and colonic epithelial morphology were assessed, and depressive behavior was analyzed one week before sampling.PD rats exhibited reduced colonic motility and GDNF expression, along with increased EGC reactivity and elevated levels of pro-inflammatory cytokines IL-1, IL-6, and TNF-α. Additionally, there was an up-regulation of CX43 and a decrease in PGP 9.5 expression. The intraperitoneal injection of AAV-GDNF significantly protected colonic neurons by inhibiting EGC activation and down-regulating CX43. This treatment also led to a notable reduction in depressive-like symptoms in PD rats with constipation.GDNF effectively reduces markers of reactive gliosis and inflammation, and promotes the survival of colonic neurons, and improves colonic motility in PD rats by regulating CX43 activity. Furthermore, GDNF treatment alleviates depressive behavior, suggesting that GDNF or its agonists could be promising therapeutic agents for managing gastrointestinal and neuropsychiatric symptoms associated with PD.

SFRP4 contributes to insulin resistance-induced polycystic ovary syndrome by triggering ovarian granulosa cell hyperandrogenism and apoptosis through the nuclear β-catenin/IL-6 signaling axis

Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by chronic ovulation dysfunction and overproduction of androgens. Women with PCOS are commonly accompanied by insulin resistance (IR), which can impair insulin sensitivity and elevate blood glucose levels. IR promotes ovarian cysts, ovulatory dysfunction, and menstrual irregularities in women patients, leading to the pathogenesis of PCOS. Secreted frizzled-related protein 4 (SFRP4), a secreted glycoprotein, exhibits significantly elevated expression levels in obese individuals with IR and PCOS. Whereas, whether it plays a role in regulating IR-induced PCOS still has yet to be understood. In this study, we respectively established in vitro IR-induced hyperandrogenism in human ovarian granular cells and in vivo IR-induced PCOS models in mice to investigate the action mechanisms of SFRP4 in modulating IR-induced PCOS. Here, we revealed that SFRP4 expression levels in both mRNA and protein were remarkably upregulated in the IR-induced hyperandrogenism with elevated testosterone in the human ovarian granulosa cell line KGN. Under normal conditions without hyperandrogenism, overexpressing SFRP4 triggered the remarkable elevation of testosterone along with the increased nuclear translocation of β-catenin, cell apoptosis and proinflammatory cytokine IL-6. Furthermore, we found that phytopharmaceutical disruption of SFRP4 by genistein ameliorated IR-induced increase in testosterone in ovarian granular cells, and IR-induced PCOS in high-fat diet obese mice. Our study reveals that SFRP4 contributes to IR-induced PCOS by triggering ovarian granulosa cell hyperandrogenism and apoptosis through the nuclear β-catenin/IL-6 signaling axis. Elucidating the role of SFRP4 in PCOS may provide a novel therapeutic strategy for IR-related PCOS therapy.

The impact and mechanism study of Sijunzi decoction and Rg1 on proliferation and differentiation of human umbilical cord mesenchymal stem cells: An experimental study.

Previous researches have demonstrated that the traditional Chinese medicine could therapeutically treat inflammatory and hypoxic diseases by enhancing the functionality of mesenchymal stem cells. However, its mechanism was not yet clear. This research aimed to investigate the impact of the traditional Chinese medicine Sijunzi decoction and its herb monomer ginsenoside Rg1 on the proliferation and differentiation of human umbilical cord mesenchymal stem cells (hUC-MSCs) and explore the underlying mechanisms. Different concentrations of Sijunzi decoction and Rg1 were applied to differentiating induced hUC-MSCs. The CCK-8 test was utilized to evaluate cell proliferation activity and identify suitable drug concentrations. Alizarin Red staining was employed to detect the formation of calcium nodules, and Oil Red O staining was used to assess the formation of lipid droplets. PCR was utilized to examine gene expression related to osteogenic differentiation, adipogenic differentiation, and the HIF-1α signaling pathway in hUC-MSCs. Western blot analysis was conducted to evaluate protein expression in osteogenic differentiation and HIF-1α. ELISA was performed to measure HIF-1α signaling factors and inflammatory cytokine expression. Biochemical assays were used to assess changes in oxidative stress indicators. The Sijunzi decoction and Rg1 both demonstrated a dose-dependent promotion of hUC-MSC proliferation. The Sijunzi decoction significantly increased the expression of genes and proteins relevant to osteogenesis, such as osterix, osteocalcin, RUNX2, and osteopontin, and activated the HIF-1α pathway in hUC-MSCs. (P < .05). Similar effects were observed at the gene level after treatment with Rg1. Simultaneously, Sijunzi decoction significantly reduced the secretion of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β, while increasing the secretion of the anti-inflammatory cytokine IL-10 during osteogenic differentiation (P < .05). Moreover, Sijunzi decoction lowered oxidative stress levels and enhanced the antioxidant capacity of hUC-MSCs during osteogenic differentiation (P < .05). However, the impact of Sijunzi decoction on hUC-MSCs toward adipogenic differentiation was not significant (P > .05). Sijunzi decoction promotes the proliferation and osteogenic differentiation of hUC-MSCs, potentially through the activation of the HIF-1α signaling pathway and by modulating the microenvironment via reducing inflammation and oxidative stress levels. Rg1 might be involved in this process.

Implication of the LRR Domain in the Regulation and Activation of the NLRP3 Inflammasome.

The NLRP3 inflammasome is a critical component of the innate immune response. NLRP3 activation is a tightly controlled process involving an initial priming to express NLRP3, pro-IL-1 β, and pro-IL-18, followed by an activation signal. The precise mechanism of activation is not fully understood due to the diverse range of activators, yet it effectively orchestrates the activation of caspase-1, which subsequently triggers the release of proinflammatory cytokines IL-1β and IL-18. NLRP3 dysregulation can lead to a variety of inflammatory diseases, highlighting its significant role in immune response and disease pathogenesis. NLRP3 is divided into three domains: the PYD, the NACHT, and the LRR domains. This review focuses on the LRR domain of NLRP3, detailing its structural characteristics, its function in pathogen sensing, its role in the degradation process, and its involvement in inflammasome auto-inhibition and activation. Additionally, we discuss the impact of mutations within the LRR domain found in atypical Cryopyrin-Associated Periodic Syndromes (CAPS), highlighting the clinical relevance of this domain.

Excessive Daytime Sleepiness, Inflammation, and Platelet Energy Metabolism in Chronic Stroke Survivors: A Pilot Study.

Excessive daytime sleepiness is a prevalent and sustained symptom that contributes to untoward physiologic and psychologic outcomes among stroke survivors. Mechanisms of excessive daytime sleepiness post-stroke are not fully understood. Chronic systemic inflammation may contribute to impaired mitochondrial functioning and thereby reduce cellular energy metabolism which may contribute to symptoms of excessive daytime sleepiness in stroke survivors. This pilot study aimed to assess the relationship between systemic inflammation and cellular energy metabolism to post-stroke excessive daytime sleepiness. This descriptive pilot study explored the relationship between excessive daytime sleepiness, systemic inflammation, and aerobic energy metabolism of platelets in 22 chronic stroke survivors. The Epworth Sleepiness Scale was used to measure excessive daytime sleepiness. Systemic inflammation was measured by assessing pro-inflammatory cytokines IL-6, IL-1β and TNF-α and the inflammatory marker C-reactive protein. Aerobic energy metabolism was measured by assessing oxygen consumption rates of platelets. Simple linear regression was used to test the influence of oxygen consumption rates and inflammation on excessive daytime sleepiness. Correlations were analyzed using Spearman rho correlation coefficients. Excessive daytime sleepiness was recognized in 27.3% of the sample. Systemic inflammation was associated with excessive daytime sleepiness in women but not men. We found no significant relationship between excessive daytime sleepiness and energy metabolism of platelets. However, all oxygen consumption rates were numerically higher in persons with excessive daytime sleepiness. Systemic inflammation may be related to excessive daytime sleepiness symptoms with a notable effect among women. Future larger studies are needed to further explore the sexually dimorphic relationship of post-stroke excessive daytime sleepiness to systemic inflammation. Numerically higher platelet oxygen consumption rates may indicate higher energy demands for stroke survivors with excessive daytime sleepiness.