Serum Levels Of Inflammatory Cytokines Research Articles

Early fluid and norepinephrine resuscitation in septic acute kidney injury diminishes pro-inflammatory cytokine levels and kidney hypoperfusion in newborn pigs

Background and Objective: Sepsis is the most frequent risk factor for acute kidney injury (AKI) in critically ill infants. Whereas sepsis-induced AKI has been studied in several animal models, alterations in renal microcirculation are unclear. The objective of this study was to use the translational swine model to evaluate the changes in renal hemodynamics during the early phase of sepsis in the first week of life. We also examined the impact of early fluid and norepinephrine (NE) resuscitation on renal hemodynamics in newborn septic AKI. Methodology: Newborn pigs (3-7 days old) were randomly allocated to three groups; 1) Sham, 2) Sepsis (cecal ligation and puncture; CLP) without subsequent resuscitation, and 3) CLP-induced sepsis with fluid and vasopressor NE resuscitation. All animals underwent standard anesthesia induction, mechanical ventilation, and intravenous fluid. Cardiac output (COP) and GFR were measured non-invasively using electrical velocimetry and a transdermal system. The pigs were instrumented to measure the mean arterial pressure (MAP), total renal blood flow (tRBF), cortical perfusion (coPf), and medullary perfusion (mePf). Also, a fiber-optic probe was placed in the medulla to measure medullary tissue oxygen tension (tPO2). Baseline values were recorded for the above indices in all groups. In resuscitated animals, fluid bolus and NE infusion were started at the 4-h to maintain MAP within 15 mmHg from baseline. The pigs were euthanized after twelve hours. Results: Compared to baseline values, MAP and COP decreased by more than two-thirds in non-resuscitated sepsis, with a proportional increase in RVR and reduction in tRBF, coPf, mePf, and tPO2 in contrast to sham. CLP also decreased GFR and increased serum creatinine, BUN, and NGAL. A few tubular coagulative necroses were observed in the septic pigs. Changes in all these parameters, except tPO2, were ameliorated in resuscitated pigs. Resuscitation also attenuated sepsis-induced increase in the levels of serum C-reactive protein, inflammatory cytokines (IL-6, IL-8, IL-12, and IL-18), liver enzymes (aspartate aminotransferase and alanine aminotransferase), and renal NLRP3 inflammasome. Conclusions: Early implementation of resuscitation to maintain MAP, COP, and kidney perfusion lessens the degree of inflammation, AKI, and liver injury in newborn pigs. The discrepancy between medullary perfusion and oxygenation indicates that optimizing perfusion and blood flow does not always correlate with improved medullary oxygen delivery in newborns, especially in cases of increased metabolic demand, as in sepsis. Sepsis is a dynamic illness with phases of hypodynamic and hyperdynamic renal perfusion; therefore, management strategies would differ based on hemodynamic status. NIH R01DK120595 and R01DK127625 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Glabridin Ameliorates Alcohol-Caused Liver Damage by Reducing Oxidative Stress and Inflammation via p38 MAPK/Nrf2/NF-κB Pathway.

Licorice is a traditional and versatile herbal medicine and food. Glabridin (Gla) is a kind of isoflavone extracted from the licorice root, which has anti-obesity, anti-atherosclerotic, and antioxidative effects. Alcoholic liver disease (ALD) is a widespread liver disease induced by chronic alcohol consumption. However, studies demonstrating the effect of Gla on ALD are rare. The research explored the positive effect of Gla in C57BL/6J mice fed by the Lieber-DeCarli ethanol mice diet and HepG2 cells treated with ethanol. Gla alleviated ethanol-induced liver injury, including reducing liver vacuolation and lipid accumulation. The serum levels of inflammatory cytokines were decreased in the Gla-treated mice. The reactive oxygen species and apoptosis levels were attenuated and antioxidant enzyme activity levels were restored in ethanol-induced mice by Gla treatment. In vitro, Gla reduced ethanol-induced cytotoxicity, nuclear factor kappa B (NF-κB) nuclear translocation, and enhanced nuclear factor (erythroid-derived 2)-like 2 (Nrf2) nuclear translocation. Anisomycin (an agonist of p38 MAPK) eliminated the positive role of Gla on ethanol-caused oxidative stress and inflammation. On the whole, Gla can alleviate alcoholic liver damage via the p38 MAPK/Nrf2/NF-κB pathway and may be used as a novel health product or drug to potentially alleviate ALD.

Lactulose regulates gut microbiota dysbiosis and promotes short-chain fatty acids production in acute pancreatitis patients with intestinal dysfunction

BackgroundIntestinal dysfunction is one of the common complications in the early stage of acute pancreatitis (AP), which often associates with bad outcome. Lactulose, as a prebiotic, has been widely used to improve gut health, yet its effect on AP is unclear. MethodsThis was a prospective, randomized trial of moderate severe AP patients complicated with intestinal dysfunction. A total of 73 participants were randomly assigned to receive either lactulose or Chinese herb rhubarb for 1 week. The primary efficacy endpoint was the recovery of intestinal function. The serum levels of inflammatory cytokines and gut barrier indexes were examined. The fecal samples from patients before and after treatment were collected. 16 S rRNA gene sequencing analysis was performed to explore the composition of gut microbiota and the amount of short-chain fatty acids (SCFAs) were detected by gas chromatography-mass spectrometry (GC-MS). ResultsThe intestinal dysfunction was prominently improved after 7 days of treatment with either lactulose or rhubarb. The serum levels of cytokines and gut permeability index were decreased after treatment, with stronger down-regulated degree in lactulose group than rhubarb. The potential beneficial genus Bifidobacterium was enriched in lactulose group, while pathogenic bacteria including Escherichia-Shigella and Neisseria were abundant in rhubarb group. Of note, the level of SCFAs was remarkably increased after treatment, with higher amount in lactulose group than rhubarb group. ConclusionsLactulose could not only restore intestinal function but also regulate gut microbiota and promote the production of SCFAs.

Inhibitory effects of Clostridium butyricum culture and supernatant on inflammatory colorectal cancer in mice.

Clostridium butyricum (CB) is a spore-forming, gram-positive and obligate anaerobic rod bacterium. CB can modulate the composition of the gut microbiome and promote the growth of beneficial microbes in the intestine by generating short-chain fatty acids (SCFAs), which in turn protect against colitis and prevents the formation of inflammatory-associated colorectal cancer (CRC) by ameliorating colon inflammatory processes. Yet, it remains unclear whether the culture and supernatant of CB could directly influence inflammatory CRC in mice. In this study, azoxymethane (AOM)+dextran sodium sulphate (DSS) was used to induce CRC model in C57BL/6 mice. Next, the serum levels of inflammatory cytokines, including interleukin-6 (IL-6), interleukin-10 (IL-10), and cytokines TNF-α, were measured and the pathohistological examination of the large intestine was performed. Both CB culture and supernatant were found to have anti-inflammatory properties. Subsequently, Western blot and Real-Time Quantitative PCR (RT-qPCR) revealed that CB and supernatant regulate the NF-κB/p65 pathway to inhibit the development and progression of inflammatory CRC in AOM+DSS-treated mice, which could be due to the high levels of butyric acid in the supernatant.

Diosmin nanocrystal gel alleviates imiquimod-induced psoriasis in rats via modulating TLR7,8/NF-κB/micro RNA-31, AKT/mTOR/P70S6K milieu, and Tregs/Th17 balance

Diosmin is a flavonoid with promising anti-inflammatory and antioxidant properties. However, it has difficult physicochemical characteristics since its solubility demands a pH level of 12, which has an impact on the drug’s bioavailability. The aim of this work is the development and characterization of diosmin nanocrystals using anti-solvent precipitation technique to be used for topical treatment of psoriasis. Results revealed that diosmin nanocrystals stabilized with hydroxypropyl methylcellulose (HPMC E15) in ratio (diosmin:polymer; 1:1) reached the desired particle size (276.9 ± 16.49 nm); provided promising colloidal properties and possessed high drug release profile. Additionally, in-vivo assessment was carried out to evaluate and compare the activities of diosmin nanocrystal gel using three different doses and diosmin powder gel in alleviating imiquimod-induced psoriasis in rats and investigating their possible anti-inflammatory mechanisms. Herein, 125 mg of 5% imiquimod cream (IMQ) was applied topically for 5 consecutive days on the shaved backs of rats to induce psoriasis. Diosmin nanocrystal gel especially in the highest dose used offered the best anti-inflammatory effect. This was confirmed by causing the most statistically significant reduction in the psoriasis area severity index (PASI) score and the serum inflammatory cytokines levels. Furthermore, it was capable of maintaining the balance between T helper (Th17) and T regulatory (Treg) cells. Moreover, it tackled TLR7/8/NF-κB, miRNA-31, AKT/mTOR/P70S6K and elevated the TNFAIP3/A20 (a negative regulator of NF-κB) expression in psoriatic skin tissues. This highlights the role of diosmin nanocrystal gel in tackling imiquimod-induced psoriasis in rats, and thus it could be a novel promising therapy for psoriasis.Graphical abstract

Alcohol extract of root and root bark of Toddalia asiatica alleviates CIA in rats through anti-inflammatory and proapoptotic effects

This study aims to investigate the therapeutic effect of alcohol extract of root and root bark of Toddalia asiatica(TAAE) on collagen-induced arthritis(CIA) in rats through phosphatidylinoinosidine-3 kinase/protein kinase B(PI3K/Akt) signaling pathway. To be specific, CIA was induced in rats, and then the rats were treated(oral, daily) with TAAE and Tripterygium Glycoside Tablets(TGT), respectively. The swelling degree of the hind leg joints was scored weekly. After 35 days of administration, the histopathological changes were observed based on hematoxylin and eosin(HE) staining. Enzyme-linked immunosorbent assay(ELISA) was employed to detect the levels of cytokines [tumor necrosis factor-α(TNF-α), interleukin(IL)-6)]. Terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL) staining was performed to detect the apoptosis of synoviocytes in rats. Western blot was used to detect the expression levels of apoptosis-related proteins B-cell lymphoma 2(Bcl-2)-associated X(Bax), Bcl-2, and caspase-3 and pathway-related proteins phosphoinositide 3-kinase(PI3K), phosphorylated(p)-PI3K, protein kinase B(Akt), and p-Akt. RT-qPCR was conducted to examine the mRNA levels of Bax, Bcl-2, caspase-3, TNF-α, IL-6, and IL-1β and pathway-related proteins PI3K, p-PI3K, Akt, and p-Akt. TAAE can alleviate the joint swelling in CIA rats, reduce serum levels of inflammatory cytokines, improve synovial histopathological changes, promote apoptosis of synoviocytes, and inhibit synovial inflammation. In addition, RT-qPCR and Western blot results showed that TAAE up-regulated the level of Bax, down-regulated the level of Bcl-2, and activated caspase-3 to promote apoptosis in synoviocytes. TAAE effectively down-regulated the protein levels of p-PI3K and p-Akt. In this study, TAAE shows therapeutic effect on CIA in rats and reduces the inflammation. The mechanism is that it suppresses PI3K/Akt signaling pathway and promotes synoviocyte apoptosis. Overall, this study provides a new clue for the research on the anti-inflammatory mechanism of TAAE and lays a theoretical basis for the better clinical application of TAAE in the treatment of inflammatory and autoimmune diseases.

Transcutaneous Electrical Acupoint Stimulation Improves Postoperative Sleep Quality in Patients Undergoing Laparoscopic Gastrointestinal Tumor Surgery: A Prospective, Randomized Controlled Trial.

This study was conducted to observe the effect of transcutaneous electrical acupoint stimulation (TEAS) on the postoperative sleep quality of patients undergoing gastrointestinal tumor surgery and to verify the possible mechanism. Eighty-three patients were allocated to the TEAS or Sham group. Patients in the TEAS group received TEAS treatment (disperse-dense waves; frequency, 2/100Hz) on bilateral Shenmen (HT7), Neiguan (PC6) and Zusanli (ST36) points for 30min each time, total three times in the perioperative period. In the Sham group, electrodes were placed; however, no current was given. Sleep quality was assessed on the day before surgery (P1) and the first and third days after surgery (D1 and D3) using the Pittsburgh Sleep Quality Index (PSQI) and Athens Insomnia Scale (AIS). Postoperative pain was assessed using visual analog scale (VAS) 72h postoperatively. The incidences of abdominal distension, dizziness, postoperative nausea and vomiting (PONV) and pulmonary complications were recorded. Serum levels of inflammatory cytokines and the expression of key factors of oxidative stress and key molecules of the nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signal pathway were measured. TEAS ameliorated sleep quality at D1 and D3 (PSQI P < 0.05, AIS P < 0.05) and decreased postoperative pain as demonstrated by lower VAS scores compared to the Sham group (P < 0.05). The incidences of abdominal distension and PONV were also lower in the TEAS group. Markers of oxidative stress were increased (P < 0.05), and the serum concentration of interleukin-6 (IL-6) was significantly lower in the TEAS group. The key mediators of the Nrf2/ARE pathway were enhanced after TEAS. Perioperative TEAS improved postoperative sleep quality, reduced postoperative pain and alleviated postoperative adverse effects in patients undergoing laparoscopic gastrointestinal tumor surgery resection. This may be associated with activating Nrf2/ARE signal pathway and decreasing its inflammatory actions. Chinese Clinical Trial Registry ( http://www.chictr.org.cn/index.aspx ), ChiCTR2100054971.

Is oxidative stress involved in the hepatic inflammatory response to apical periodontitis? A comparative study in normal and hyperlipidaemic rat.

The aim of the study was to explore the involvement of oxidative stress (OS) in the hepatic inflammation induced by apical periodontitis (AP). Periapical, systemic and hepatic reaction to AP under hyperlipidaemia was also investigated. A total of 16 male Sprague-Dawley rats were fed with a hyperlipidaemic diet (HD) whereas another 16 rats with a normal diet (ND). After 9 weeks, the first molars of the right maxilla and mandible of 8 HD and 8 ND rats were exposed to induce AP (ND, ND + AP, HD and HD + AP group). After 5 weeks, rats were euthanized, the haematological tissue was collected directly from the heart, and serum levels of inflammatory cytokines were measured. Liver tissue was analysed by haematoxylin-eosin and Masson staining, and reverse transcription-polymerase chain reaction (RT-PCR) was performed to detect mRNA expression of inflammatory cytokines. Serum, periapical, and hepatic OS parameters including total oxidant status (TOS), total antioxidant capacity (TAOC) and oxidative stress index (OSI) were measured by enzyme-linked immunosorbent assay (ELISA). The area of AP lesion in the right maxilla or mandible was radiographically assessed. Student's t-test was performed on the periapical data. A one-way analysis of variance and the Kruskal-Wallis test were analysed for others. The HD + AP group had a larger AP lesion in the maxilla, compared with the ND + AP group (p < .05). The ND + AP group presented higher serum interleukin (IL)-18, IL-1β, TOS, OSI levels, lower serum TOAC levels, higher hepatic tumour necrosis factor (TNF)-α mRNA expression and higher hepatic TOS, and OSI levels, compared with the ND group (p < .05). The HD + AP group had lower serum IL-4 level, higher serum IL-1β level, and higher hepatic IL-6 and transforming growth factor (TGF) -β1 mRNA expression, compared with the HD group (p < .05). Apical periodontitis could activate systemic and liver inflammation by promoting serum IL-18, 1L-1β, TOS and OSI expression, enhancing hepatic TOS and OSI expression and inhibiting serum TOAC expression. AP under hyperlipidaemia led to more profound periapical bone destruction in the maxilla and elicit systemic and liver inflammatory responses through elevating serum levels of IL-1β, descending serum IL-4 level and improving hepatic IL-6 and TGF-β1 expression.

Effect of Sertraline on Serum Cytokine Levels in Adolescents With First-Episode Major Depressive Disorder

To investigate the changes in serum inflammatory cytokines and the predictive factors for the efficacy of sertraline following medication therapy in adolescents with first-episode major depressive disorder (MDD). A total of 61 adolescent patients with first-episode drug-naïve MDD were enrolled for the MDD group and 55 healthy adolescents were enrolled for the healthy control (HC) group. Sertraline tablets were administered to the MDD group for 8 weeks after enrollment, while no medication was given to the HC group. In the MDD group, blood samples were collected to measure the cytokine levels and clinical data, including scores for the 17-item Hamilton Depression Scale (HAMD-17) and the Connor-Davidson Resilience Scale (CD-RISC), were assessed at baseline and at the end of the 8-week medication, whereas in the HC group, blood samples and clinical data were collected only at baseline. The correlation between the levels of serum inflammatory cytokines and depression severity in the MDD group was analyzed and stepwise linear regression of HAMD-17 in the MDD group was performed to find serologic indicators that could be used to predict the efficacy of sertraline. At baseline, the levels of interleukin (IL)-1β and IL-6 in the MDD group were significantly higher than those in the HC group (all P<0.0001), while the tumor necrosis factor (TNF)-α level in the MDD group was significantly lower than that in the HC group ( P=0.006). After 8 weeks of medication treatment, the MDD group showed decreased levels of IL-1β and IL-6 and increased level of TNF-α compared to the pre-treatment levels. In addition, the HAMD-17 score, CD-RISC total score, and scores for perceived competence, trust and tolerance, and control, three factors of CD-RISC, all improved after treatment. There was no significant difference in serum cytokine levels at baseline between the subgroup showing response to the treatment and the non-responding subgroup. There was a weak correlation between IL-6 levels before and after treatment and CD-RISC scores and the scores for the trust and tolerance factor of CD-RISC before and after treatment. The baseline IL-1β and TNF-α levels did not show significant effect on posttreatment HAMD-17 scores. Serum cytokine levels of adolescents with first-episode MDD differ significantly from those of healthy adolescents. Although IL-6 was found to be correlated with depression severity, there was not enough support for it to be used as a predictor of the antidepression efficacy of sertraline.

Necrostatin-1 Alleviates Diffuse Pulmonary Haemorrhage by Preventing the Release of NETs via Inhibiting NE/GSDMD Activation in Murine Lupus.

Diffuse alveolar haemorrhage (DAH) is a rapidly developing condition owing to a lack of effective treatment and resulting in a high mortality rate in systemic lupus erythematosus (SLE). Neutrophil extracellular traps (NETs) contain numerous antigens and proinflammatory substances that directly damage the vascular endothelium and aggravate vascular inflammation, which is considered an important pathogenic factor of DAH in SLE. Therefore, blocking the release of NETs from neutrophils is an important target for the treatment of DAH in SLE. In this study, we investigated whether the inhibition of neutrophils releasing NETs could relieve DAH in SLE. Necrostatin-1 (Nec-1), a small molecule, has been reported to inhibit the release of NETs by neutrophils. In vitro experiments revealed that Nec-1 inhibited alveolar epithelial cell damage by preventing the release of NETs. Furthermore, vivo studies showed that Nec-1 alleviated lupus pulmonary haemorrhage in mice by reducing lung pathology severity, body weight, and serum inflammatory cytokine levels. Mechanistically, Nec-1 prevented NET release by inhibiting neutrophil elastase (NE) activation and N-Gasdermin D (N-GSDMD) expression. Additionally, immunohistochemistry and immunofluorescence findings showed that Nec-1 decreased NE expression in the lung tissues of mice with lupus pulmonary haemorrhage. Thus, NETs released by neutrophils contributed to the pathogenesis of DAH in SLE, and Nec-1 showed protective effects by the inhibition of NET production via the reduction of NE activation and N-GSDMD expression.

Serum LL-37 and inflammatory cytokines levels in psoriasis.

Psoriasis (PsO) is a T-cell-associated inflammatory autoimmune dermatitis. Leucine leucine-37 (LL-37) is upregulated in PsO patients and correlated with the area and severity of PsO. However, the exact relation between LL-37 and T cell-associated inflammation is not well understood. It is very important to clarify the relationship between LL-37 and inflammatory response for clinical diagnosis and treatment of PsO. This study investigated the serum levels of LL-37 and inflammatory cytokines, as well as correlations between them in PsO patients, which aimed to provide new ideas for the diagnosis and treatment of PsO. PsO patients (n = 50) and healthy volunteers (n = 33) were recruited in this study. Skin specimens were stained with hematoxylin and eosin (H&E). The serum levels of LL-37, T-helper type 1 (Th1, IFN-γ), T-helper type 17 (Th17, IL-17), T-helper type 22 (Th22, IL-22), and T-helper type 2 cytokines (Th2, IL-4) were assessed by enzyme-linked immunosorbent assay. Some of the patients were re-recruited after treatment to evaluate LL-37 and cytokines levels. Pathological changes were observed in PsOskin lesions. LL-37, IFN-γ, IL-17, and IL-22 serum levels were much higher in PsO patients than those in healthy volunteers (p < .001), and posttreatment reduction was observed in five patients. However, no remarkable difference in IL-4 level (p > .05) was found. LL-37 level was positively correlated with IFN-γ, IL-17, and IL-22 levels (p < .001) in PsO patients. LL-37 expression was significantly associated with inflammatory response, which may provide us new ideas for diagnosing and monitoring disease activity of PsO.

Emblica officinalis mitigates intestinal toxicity of mice by modulating gut microbiota in lead exposure

Lead (Pb) contamination has been affecting public health for decades. As a plant-derived medicine, the safety and effectiveness of Emblica officinalis (E. officinalis) fruit extract has been emphasized. The current study focused on mitigating the adverse effects of lead (Pb) exposure in reducing its toxicity worldwide. According to our findings, E. officinalis significantly improved weight loss and colon length shortening (p < 0.05 or p < 0.01). The data of colon histopathology and serum levels of inflammatory cytokines indicated a positive impact to the colonic tissue and inflammatory cell infiltration in a dose-dependent manner. Moreover, we confirmed the expression level improvement of tight junction proteins (TJPs), including ZO-1, Claudin-1, and Occludin. Furthermore, we found that the abundance of some commensal species necessary for maintaining homeostasis and other beneficial function decreased in Pb exposure model, while a remarkable reversion impact was noticed on the intestinal microbiome composition in the treatment group. These findings were consistent with our speculations that E. officinalis could mitigate the adverse effects caused by Pb in alleviating intestinal tissue damage, intestinal barrier disruption, and inflammation. Meanwhile, the variations in gut microbiota might drive the fulfilling current impact. Hence, the present study could provide the theoretical basis for mitigating intestinal toxicity induced by Pb exposure with the help of E. officinalis.

Anlotinib Alleviates Renal Fibrosis via Inhibition of the ERK and AKT Signaling Pathways.

We examined whether anlotinib can attenuate folic acid-induced and unilateral ureteral obstruction-induced renal fibrosis and explored the underlying antifibrotic mechanism. We have evaluated the effects of anlotinib on folic acid-induced and unilateral ureteral obstruction-induced renal fibrosis in mice through in vivo experiments of unilateral ureteral obstruction or folic acid-induced interstitial fibrosis and in vitro models of transforming growth factor-β1 induced HK-2 human renal proximal tubule cells. Serum renal function parameters and inflammatory cytokine levels were measured, and histological changes of renal injury and fibrosis were analyzed by HE staining and immunohistochemistry. Immunohistochemistry and Western blotting were used to determine the mechanism of action of anlotinib in ameliorating renal fibrosis. Anlotinib improved proteinuria and reduced renal impairment in folic acid-induced mouse models of renal fibrosis. Anlotinib reduced tubular injury, deposition of tubular extracellular matrix, and expression of alpha-smooth muscle actin, transforming growth factor-β1, and cytosolic inflammatory factors compared with controls. Anlotinib ameliorated renal function, improved extracellular matrix deposition, reduced protein levels of epithelial-mesenchymal transition markers, and decreased cellular inflammatory factors. Anlotinib reduced renal injury and fibrosis by inhibiting the transforming growth factor-β1 signaling pathway through AKT and ERK channels.

Serum inflammatory cytokines levels and the correlation analyses in Parkinson's disease.

Objective: To investigate the serum levels of inflammatory cytokines and the correlations with Parkinson's disease (PD) clinical symptoms. Methods: Serum levels of the cytokines, including IL-6, IL-8, and TNF-α, were measured in 273 PD patients and 91 healthy controls (HCs). The clinical manifestations of PD were assessed with nine different scales to evaluate the cognitive function, non-motor symptoms, motor symptoms, and disease severity. The differences in these inflammatory indicators were examined between PD patients and HCs, and the correlations of these inflammatory indicators with clinical variables were analyzed in PD patients. Results: Serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in PD patients were higher than those in HCs, but serum interleukin-8 (IL-8) level was not significantly different from that in HCs. In PD patients, serum IL-6 level was positively correlated with age of onset, the Hamilton Depression Scale (HAMD), and the Non-Motor Symptom Scale (NMSS), UPDRS part I, part II, and part III, but it was inversely correlated with the Frontal Assessment Battery (FAB) and the Montreal Cognitive Assessment (MoCA) scores. Serum TNF-α level was positively correlated with age of onset and H&Y stage in PD patients (p = .037), but negatively correlated with FAB scores in PD patients (p = .010). However, no associations were found between all the clinical variables and the serum IL-8 level. The forward binary logistic regression model revealed that serum IL-6 level was associated with MoCA (p = .023) and UPDRS I scores (p = .023), but no associations was found with the remaining factors. The ROC curve of TNF-α for the diagnosis of PD showed the area under the curve (AUC) was .719 (p < .05, 95% CI: .655-.784), and the critical value of TNF-α was 5.380pg/ml, with a diagnostic sensitivity of 76.0% and a specificity of 59.3%. Conclusion: Our results suggest increased serum levels of IL-6 and TNF-α in PD, we further found that IL-6 level was associated with non-motor symptoms and cognitive dysfunction, and IL-6 may play a role in the pathophysiology of non-motor symptoms in PD. At the same time, we also propose that TNF-α has a good diagnostic value for PD despite its irrelevance to clinical symptoms.

Changes in Inflammatory Markers in Clinical High Risk of Developing Psychosis

Introduction: Immune alterations are associated with the progression of psychosis. However, there are few studies designed to longitudinally measure inflammatory biomarkers during psychotic episodes. We aimed to assess changes in biomarkers from the prodromal phase to psychotic episodes in individuals with clinical high risk (CHR) of psychosis and compare converters and non-converters to psychosis as well as healthy controls (HCs). Methods: We enrolled 394 individuals with CHR and 100 HCs. A total of 263 individuals with CHR completed the 1-year follow-up, and 47 had converted to psychosis. Interleukin (IL)-1β, 2, 6, 8, 10, tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor levels were measured at baseline and 1 year after completion of the clinical assessment. Results: The baseline serum levels of IL-10, IL-2, and IL-6 were significantly lower in the conversion group than in the non-conversion group (IL-10, p = 0.010; IL-2, p = 0.023; IL-6, p = 0.012) and HC (IL-6: p = 0.034). Self-controlled comparisons showed that IL-2 changed significantly (p = 0.028), and IL-6 levels tended toward significance (p = 0.088) in the conversion group. In the non-conversion group, serum levels of TNF-α (p = 0.017) and VEGF (p = 0.037) changed significantly. Repeated measures analysis of variance revealed a significant time effect related to TNF-α (F = 4.502, p = 0.037, effect size (η²) = 0.051), a group effect related to IL-1β (F = 4.590, p = 0.036, η² = 0.062), and IL-2 (F = 7.521, p = 0.011, η² = 0.212), but no time × group effect. Discussion: Alterations in the serum levels of inflammatory cytokines were found to precede the first episode of psychosis in the CHR population, particularly for those who later converted to psychosis. Longitudinal analysis supports the varied roles of cytokines in individuals with CHR with later psychotic conversion or non-conversion outcomes.

The soluble epoxide hydrolase inhibitor TPPU improves comorbidity of chronic pain and depression via the AHR and TSPO signaling

BackgroundPatients suffering from chronic pain often also exhibit depression symptoms. Soluble epoxide hydrolase (sEH) inhibitors can decrease blood levels of inflammatory cytokines. However, whether inhibiting sEH signaling is beneficial for the comorbidity of pain and depression is unknown.MethodsAccording to a sucrose preference test (SPT), spared nerve injury (SNI) mice were classified into pain with or without an anhedonia phenotype. Then, sEH protein expression and inflammatory cytokines were assessed in selected tissues. Furthermore, we used sEH inhibitor TPPU to determine the role of sEH in chronic pain and depression. Importantly, agonists and antagonists of aryl hydrocarbon receptor (AHR) and translocator protein (TSPO) were used to explore the pathogenesis of sEH signaling.ResultsIn anhedonia-susceptible mice, the tissue levels of sEH were significantly increased in the medial prefrontal cortex (mPFC), hippocampus, spinal cord, liver, kidney, and gut. Importantly, serum CYP1A1 and inflammatory cytokines, such as interleukin 1β (IL-1β) and the tumor necrosis factor α (TNF-α), were increased simultaneously. TPPU improved the scores of mechanical withdrawal threshold (MWT) and SPT, and decreased the levels of serum CYP1A1 and inflammatory cytokines. AHR antagonist relieved the anhedonia behaviors but not the algesia behaviors in anhedonia-susceptible mice, whereas an AHR agonist abolished the antidepressant-like effect of TPPU. In addition, a TSPO agonist exerted a similar therapeutic effect to that of TPPU, whereas pretreatment with a TSPO antagonist abolished the antidepressant-like and analgesic effects of TPPU.ConclusionssEH underlies the mechanisms of the comorbidity of chronic pain and depression and that TPPU exerts a beneficial effect on anhedonia behaviors in a pain model via AHR and TSPO signaling.

Cardioprotective Effects of Octreotide against Sepsis-Induced Cardiotoxicity in Mice.

Sepsis is a systemic inflammatory consequence resulting from microbial infection, assessed as a worldwide healthcare issue. Sepsis can result in multiorgan dysfunction, including cardiac, renal, hepatic, and cerebral dysfunction. Cardiotoxicity can occur in humans and rodents during sepsis, leading to increased mortality. The current study aims to explore the possible cardioprotective effects of octreotide during sepsis-induced cardiotoxicity. This study was done with a total of forty male albino Swiss mice, aged 8-12 weeks and weighing 25-30 gm. These animals had free access to food and water. After two weeks of adaptation, mice were divided into four groups (n=10): 1) Normal group: healthy mice; 2) CLP group: mice underwent CLP operation; 3) Vehicle group: mice received DMSO. 4) Octreotide group: mice received octreotide (10 mg/kg) subcutaneously in 2 divided doses for 5 consecutive days. All groups underwent CLP operation on the 4th day, then sacrificed on the 5th day then blood, and tissue sampling was done. The Octreotide group demonstrated a significant (P<0.05) decrease in the myocardial levels of cardiac troponin-I as compared to the CLP group. Furthermore, the octreotide group demonstrated a significant (P<0.05) decrease in the serum level of inflammatory cytokines (TNF-α, IL-6, & IL-1β) as compared to the CLP group. Additionally, the octreotide group showed a significant (P<0.05) elevation in the myocardial activity of SOD and a reduction in MDA level compared to the CLP group. Histologically, all mice in the CLP group showed a significant (P<0.05) cardiac tissue injury, while the octreotide groups showed a significant (P<0.05) reduced level of cardiac tissue injury. The results of the present study revealed that octreotide attenuates sepsis-induced cardiotoxicity through different protective effects; they include the anti-inflammatory effect through their ability to decrease serum levels of inflammatory cytokines (TNF-α, IL-1β, and IL-6). Also, the anti-oxidant effect through their ability to decrease myocardial levels of MDA and increase the myocardial activity of SOD. Additionally, the direct cardiac protective effect through the lower level of cardiac troponin- I and the reduction of histopathological changes during sepsis-induced cardiotoxicity.

Cystic Fibrosis Transmembrane Conductance Regulator Attenuates Oxidative Stress-Induced Injury in Diabetic Retinopathy Rats

Purpose To investigate the effects of cystic fibrosis transmembrane conductance regulator (CFTR) on oxidative stress-induced injury of diabetic retinopathy (DR) rats. Methods DR rat model was constructed treated with Ad-CFTR. Hematoxylin and Eosin (HE) staining was applied for testing the thickness of each layer of retinal tissues. Enzyme-linked immunosorbent assay (ELISA) was used to determine levels of serum inflammatory cytokines and contents of oxidative stress related genes in rats. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) staining was used to detect retinal cell apoptosis, and western blotting to measure the expression of MAPK/NF-κB pathway-related proteins in retinal tissues. Results Our experiment revealed the remarkable decrease of CFTR protein in retinal tissues of DR rats. DR rats had decreased body weight and increased blood glucose level, with decreased thickness of total retinal thickness (TRT), outer nuclear layer and outer plexiform layer (ONL + OPL), inner nuclear layer (INL), and inner plexiform layer (IPL). Besides, DR rats were apparently up-regulated in the expression of pro-inflammatory cytokines, with increased malondial dehyde (MDA), p-ERK1/2/ERK1/2 and p-JNK1/2/JNK1/2 expressions, decreased superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity in retinal tissues, as well as up-regulated p65 protein in nucleus and down-regulated p65 protein in cytoplasm. DR rats treated with Ad-CFTR were effectively improved regarding the above parameters except body weight and blood glucose. Conclusions CFTR can inhibit MAPK/NF-κB signaling pathway to ameliorate inflammatory response and oxidative stress-induced injury of DR rats, thereby reducing retinal cell apoptosis and playing a protective role in retina.

Nano Parthenolide Improves Intestinal Barrier Function of Sepsis by Inhibiting Apoptosis and ROS via 5-HTR2A.

Intestinal barrier dysfunction is an important complication of sepsis, while the treatment is limited. Recently, parthenolide (PTL) has attracted much attention as a strategy of sepsis, but whether nano parthenolide (Nano PTL) is therapeutic in sepsis-induced intestinal barrier dysfunction is obscured. In this study, cecal ligation and puncture (CLP)-induced sepsis rats and lipopolysaccharide (LPS)-stimulated intestinal epithelial cells (IECs) were used to investigate the effect of PTL on intestinal barrier dysfunction. Meanwhile, we synthesized Nano PTL and compared the protective effect of Nano PTL with ordinary PTL on intestinal barrier function in septic rats and IECs. Network pharmacology and serotonin 2A (5-HTR2A) inhibitor were used to explore the mechanism of PTL on the intestinal barrier function of sepsis. The encapsulation rate of Nano PTL was 95±1.5%, the drug loading rate was 11±0.5%, and the average uptake rate of intestinal epithelial cells was 94%. Ordinary PTL and Nano PTL improved the survival rate and survival time of septic rats, reduced the mean arterial pressure and the serum level of inflammatory cytokines, and protected the liver and kidney functions in vivo, and increased the value of transmembrane resistance (TEER) reduced the reactive oxygen species (ROS) and apoptosis in IECs in vitro through 5-HTR2A. Nano PTL had better effect than ordinary PTL. Ordinary PTL and Nano PTL can protect the intestinal barrier function of septic rats by inhibiting apoptosis and ROS through up-regulating 5-HTR2A, Nano PTL is better than ordinary PTL.

Possible Role of Leukemia Inhibitory Factor and Inflammatory Cytokines in The Recurrent Spontaneous Abortion: A Case-Control Study.

Despite of long-lasting efforts, in more than 50% of cases, the etiology of recurrent spontaneous abortion (RSA) remains unknown. Leukemia inhibitory factor (LIF) has an essential role in the reproductive process, such as modulating inflammatory responses. This study aimed to evaluate the relationship between the LIF gene expression as well as serum levels of inflammatory cytokines and occurrence of RSA in infertile women with a history of RSA. In this case-control study, the relative gene expression levels of LIF, concentrations of tumor necrosis factor-alpha (TNF-α), and interleukin (IL)-17 were measured in peripheral blood and serum of women with a history of RSA (N=40) compared with non-pregnant and fertile women as the control group (N=40) using quantitative real-time polymerase chain reaction and the enzyme-linked immunosorbent assay, respectively. The mean age of patients and controls was 30.1 ± 4.28 and 30.03 ± 4.23, respectively. Patients had a history of at least 2 and at most 6 abortions. The mRNA levels of LIF were significantly lower in the women with RSA in comparison with the healthy participant (P=0.003). Regarding cytokine levels, no significant difference was seen between the two groups (P≥0.05). There was no correlation - between the LIF mRNA levels and TNF-α and IL-17 serum concentrations. The U-Mann-Whitney test and the Pearson correlation coefficient were applied to comparison variables between groups as well as a correlation between LIF mRNA and cytokine levels in serum. Despite a significant reduction in the LIF gene mRNA level in patients with RSA, it was not associated with increases in inflammatory cytokines. Dysfunction in the production of LIF protein may be involved in the onset of RSA disorder.