Changes In Inflammatory Markers Research Articles

Arctiin Protects Chondrocytes From Interleukin-1β-Induced Inflammation and Apoptosis by RNA Sequence In vivo and In vitro

Abstract Objective: Osteoarthritis (OA) is a progressive joint disease characterized by degeneration and destruction of articular cartilage. Arctiin (ARC) has been shown in many studies to have potential anti-inflammatory, anti-apoptotic, and antioxidant effects in various diseases. However, the mechanism by which ARC exerts its protective effects in OA is not fully understood. Here, we explore the mechanism by which ARC plays its protective role in OA. Materials and Methods: Mouse chondrocytes were isolated and characterized through toluidine blue staining and collagen II immunofluorescence labeling. A mouse-based experimental model was developed to induce chondrocyte inflammation through Interleukin-1β (IL-1β). Subsequently, ARC was administered in various doses to mitigate this inflammation. Techniques such as biochemical assays, Enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, and immunofluorescence labeling were employed to detect changes in nitric oxide (NO), lactate dehydrogenase (LDH), inflammatory markers, and components of the cartilage matrix in chondrocytes. RNA-sequencing (RNA-seq) was utilized to explore variations in gene expression among chondrocytes across different groups. The genes and signaling pathways that were identified underwent analysis through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment studies. Validation of gene and protein expression was carried out using qRT-PCR, Western blotting, and cellular flow cytometry, based on the results from sequencing. Furthermore, Safranin-O fast green staining and immunohistochemistry staining were performed on slices of the mice knee joint to evaluate the OA Research Society International score, alterations in the cartilage matrix, and levels of apoptosis-related proteins at sites of knee cartilage damage in an arthritis model induced by monosodium iodoacetate (MIA) and physical activity. Results: It was found that ARC effectively inhibits the production of IL-1β-induced chondrocytes’ inducible NO synthase, cyclooxygenase-2, NO, LDH, IL-6, and tumor necrosis factor-α. ARC exhibited a dose-dependent effect on chondrocytes by reducing IL-1β-induced matrix metalloproteinase-3 (MMP-3) and a disintegrin and metalloproteinase with thrombospondin motifs-5 levels while increasing Aggrecan levels. RNA-seq and bioinformatics analysis revealed that ARC’s therapeutic effects involve apoptotic signaling pathways through the downregulation of Bcl-2-associated X protein (Bax) and caspase-3 expression and the upregulation of B-cell lymphoma-2 (Bcl-2) expression in IL-1β-induced chondrocytes. ARC significantly raised the levels of aggrecan and Bcl-2 and decreased the levels of MMP-3, Bax, and caspase-3 in an arthritis model induced by MIA and movement. Conclusions: Through RNA-seq, in vitro cell assays, and in vivo experiments, this research established the link between apoptosis and inflammation in the progression of OA and confirmed the protective effects of ARC on chondrocytes and its key targets. This highlights ARC’s therapeutic potential and its role in the development of treatments for OA.

Evaluation of the Efficacy and Safety of Intravenous Immunoglobulin (IVIG) in Moderate-to-Severe Hospitalized COVID-19 Patients: A Randomized, Open-Label Parallel-Group Study.

Since February 2020, the world has been overwhelmed by the SARS-CoV-2 outbreak, and several patients suffered interstitial pneumonia and respiratory failure requiring mechanical ventilation, threatening the capability of healthcare systems to handle this amount of critical cases. Intravenous immunoglobulins (IVIG) possess potential immunomodulatory properties beneficial for COVID-19 patients, yet evidence supporting IVIG as adjunctive therapy remains sparse. This study evaluated the outcomes of adjunctive IVIG with the standard of care (SoC) in moderate-to-severe COVID-19 patients. This randomized study included 59 moderate-to-severe COVID-19 patients with known comorbidities. One arm (n = 33) received high-dose IVIG (400 mg/kg/day) within 48 hours for five days alongside SoC, while the other arm (n = 26) received SoC, comprising steroids, enoxaparin, and remdesivir. The primary endpoint was clinical improvement, as measured by the National Early Warning Score 2 (NEWS2) and discharged/death proportions. Secondary outcomes included IVIG safety, hospitalization duration, changes in oxygen saturation, inflammatory markers, IgG titer, CTSS (CT severity score), and radiological findings. There was an improvement in the NEWS2 at the end of treatment in the IVIG arm (5.67 vs. 5.96). A significant absolute effect improvement (Day 1 vs. Day 9) was seen in serum LDH, D-dimer, hs-CRP, IL-6, CTSS, procalcitonin, respiratory rate, and chest radiographic findings. SARS-CoV-2 IgG titer increased significantly in the IVIG arm. There was a statistically significant reduction in mortality in the IVIG group (5 vs. 10). IVIG was a safe and effective adjunctive therapy to SoC treatment in moderate-to-severe COVID-19 patients needing ventilatory support. Furthermore, studies are required to validate our findings. This trial is registered with CTRI/2021/05/033622.

Abstract PO3-19-02: White Button Mushroom and Biomarkers of Immune Cell and Inflammatory Responses in Obese Postmenopausal Women at High Risk of Breast Cancer

Abstract Background: White Button Mushroom (WBM), Agaricus bisporus, has anti-tumor and anti-inflammatory effects. Oral WBM mitigated the effects of a high fat diet on hepatic steatosis and insulin resistance in ovariectomized mice. A Phase I trial of WBM in men with prostate cancer demonstrated decreased myeloid derived suppressor cells (MDSC) in those with decreased PSA; MDSC have been linked to different cancers, including breast, and conditions of chronic inflammation. Design: This is a preliminary evidence trail in postmenopausal, obese women at high risk of breast cancer with a single intervention arm of 14g of WBM taken as 28 tablets daily for 3 months to assess effects on inflammation. Participants undergo a physical exam, measuring height, weight, and waist circumference, an optional fine needle aspiration (FNA) of breast tissue, a blood draw, a food frequency questionnaire and a 24-hour food recall at baseline and final visits. Participants are contacted monthly for tolerance and adherence. Blood samples and FNA adipose are used for metabolic measurements and processed for biomarkers of inflammation and immune response. Peripheral blood mononuclear cells (PBMC) will be used for RNA single-cell analysis to assess for immune cell profiles and expression with an interest in evaluating MDSC. Red blood cells will be assessed for fatty acid profiles. Eligibility: Postmenopausal, obese (BMI ≥30, Asian ≥25) women with high risk for breast cancer who can swallow pills are eligible. Patients are high risk if their relative risk of breast cancer is ≥2 times that of the general population; this includes women with a strong family history, a genetic mutation associated with hereditary breast cancer, a high-risk breast histology, Gail model 5-year risk >1.67, or a previous history of stage I-II breast cancer. Participants are excluded for an active malignancy within 5 years, ongoing active or preventative cancer treatment, or lab abnormalities of serum creatinine and total bilirubin >1.5 the upper limit of normal, hemoglobin of < 9.0 g/dL, platelets of < 100,000/mm3, or a total white blood cell count of < 3,500/mm3. Participants cannot be taking mushroom supplements, immunosuppressants, or non-steroidal anti-inflammatories. Specific Aims: This study aims to evaluate the effects of WBM on regulating immune response and inflammation in obese women at high risk for breast cancer. Our primary objective is the assessment of PBMC, specifically MDSC immune profiles before and after treatment. Our secondary objective is to evaluate changes in biomarkers of inflammation, immune cell profiles in breast adipose tissue, BMI, waist circumference, and metabolic biomarkers. Additionally, the study aims to assess tolerability of the WBM dose and effects on diet quality. Statistical Methods: 26 patients will provide 80% power to detect a change in %MDSC of -0.67, assuming a standard deviation of 1.15, and a 2-sided type I error of 5%. We will have similar power to evaluate changes in other immune subsets, inflammatory markers, metabolic markers, anthropometric measurements, and diet quality. FNA adipose tissue analysis will be used as a safety signal to evaluate the potential for unwanted inflammation with taking WBM. 13 patients with FNA will provide 80% power to detect a change of 85% of the standard deviation of the difference in the measure of biomarkers such as Interleukin-6 with a 2-sided type I error of 5%. As a safety signal, the signal will be reported without adjustment for multiple comparisons. Any conclusions based on such secondary endpoints will make note of the multiple comparison issue. Accrual: The accrual target is 26 evaluable patients with an estimated need to enroll 31. The study has enrolled 27 patients, 14 completed the study and 5 are currently on treatment. 8 participants were removed; 3 never started treatment, 1 was diagnosed with breast cancer, and 4 had other medical issues preventing continuation. Contact: Jessica Dzubnar, MD: jdzubnar@coh.org Citation Format: Jessica Dzubnar, Lisa Yee, Shiuan Chen. White Button Mushroom and Biomarkers of Immune Cell and Inflammatory Responses in Obese Postmenopausal Women at High Risk of Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-19-02.

Logistic regression model predicts early surgical site infection after spinal fusion: a retrospective cohort study

This study aimed to develop a diagnostic model for predicting early surgical site infection based on postoperative inflammatory markers after spinal fusion surgery. In this retrospective study, we analysed the trends of inflammatory markers between surgical site infection (SSI) group and non-SSI group. The data were randomly divided into training cohort and validation cohort (ratio 7:3). The variables for SSI were analysed using stepwise logistic regression to develop prediction model. To evaluate the model, we analysed its sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), as well as the area under curve (AUC) in the validation cohort. Calibration plots and decision curve analysis (DCA) were employed to assess the calibration and clinical usefulness of the model. We observed significant changes in inflammatory markers on the seventh day after surgery. The prediction model included four variables on the seventh day after surgery: body temperature, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and neutrophil counts. After binary processing of these data, the simplified model achieved an AUC of 0.86 (CI 95%: 0.81-0.92) in the training cohort and 0.9 (CI 95%: 0.82-0.98) in the validation cohort. Calibration plots and DCA demonstrated that the proposed model was effective for the diagnosis of SSI. We developed and validated a prediction model for diagnosing early infection after spinal fusion.

Systemic Inflammatory Markers and Clinical Outcomes of Open versus Biportal Endoscopic Transforaminal Lumbar Interbody Fusion.

The purpose of this study is to preliminarily assess the change in perioperative systemic inflammatory markers and clinical outcomes between open TLIF and BE-TLIF procedures. In total, 38 patients who underwent single-level lumbar fusion surgery (L4-5 or L5-S1) were retrospectively reviewed. 19 patients were treated by the BE-TLIF technique, while the other patients were managed using open TLIF. The perioperative serum C-reactive protein (CRP), neutrophil/lymphocyte ratio (NLR), lymphocyte/monocyte ratio (LMR), and platelet/lymphocyte ratio (PLR) of the two groups were compared to determine if there was a statistical difference. Meanwhile, clinical evaluations were conducted to assess various factors including operative duration, estimated blood loss (EBL), drainage catheter stay, length of hospitalization, visual analogue scale (VAS), and Oswestry disability index (ODI) scores. The perioperative analysis revealed that BE-TLIF cases experienced a longer operative duration than open TLIF cases (open TLIF: 138.63 ± 31.59 min, BE-TLIF: 204.58 ± 49.37 min, p < 0.001). Meanwhile, the EBL showed an increased trend in the BE-TLIF group (260.7 ± 211.9 mL) in comparison with the open TLIF group (200.9 ± 211.9 mL) (p =0.485). In terms of systemic inflammatory markers, the mean postoperative CRP, NLR, LMR, and PLR were lower in the BE-TLIF group than in the open TLIF group, although these differences were not statistically significant (p > 0.05). The VAS and ODI scores in both groups were significantly improved after surgery (p < 0.05). There was no significant difference found between BE-TLIF and open TLIF in terms of systemic inflammatory markers, and clinical outcomes. Overall, BE-TLIF can be considered a viable choice for lumbar canal decompression and interbody fusion for less invasion. It is worth noting that BE-TLIF does have a longer operation time, indicating that there is still potential for further improvement in this technique.

Temporal variations in immune and inflammatory markers following rodent juvenile traumatic brain injury

Traumatic brain injury (TBI) is one of the leading causes of death and disability in the juvenile population. TBI is associated with elevations in inflammatory signaling. However, the temporal changes in immune and inflammatory markers following TBI, particularly in juvenile studies utilizing the Closed Head Injury Model of Engineered Rotational Acceleration (CHIMERA), have not been fully elucidated. The current study aimed to determine the time course of changes to immune cell expression throughout the first four days following juvenile TBI via the CHIMERA. Male Long Evans rats sustained either a TBI or a Sham TBI via the CHIMERA on post-natal day (PND) 30. Sham animals were euthanized at 3 hours (h) post-injury. TBI animals were euthanized at 0, 3, 6, 12, 24, or 96 h post-injury. Hippocampus samples were collected for use in QRT-PCR. The mRNA expression of cytokines IL1b and TNF-α was significantly elevated at 6 h, and C1q C chain (C1QC), a dendritic cell marker, was significantly elevated at 24 h. The mRNA expression of CD68, a marker for macrophages, was significantly elevated at 6, 24, and 96 h post-injury compared to Sham. CD3G, a marker for T cells, was significantly elevated at 6 hours post-injury. However, the mRNA expression of PTPRC, a marker for leukocytes, was not significantly altered throughout the time periods evaluated. To follow up on these studies, juvenile rats were injured and brains and blood were harvested 48 h post-injury comparing Sham and TBI. Peripheral blood lymphocytes were obtained and sorted by marker-specific antibodies. In the peripheral blood, there was a significantly higher number of CD3+ total T cells, CD3+/CD8 cytotoxic T cells, and CD3+/CD4+ helper T cells in the TBI group compared to the Sham, but CD45R+ total B cells and natural killer (NK) cells were not significantly different. Superior hemi-sected cortices were also used for immune cell extraction. There was a significantly lower number of NK cells and CD45R+ total B cells in the TBI group compared to the Sham, but CD45+ leukocytes and CD3+ total T cells were not significantly different. Further work is needed to understand the relationship between the reduction of specific cells in the brain with the elevation of cells in the peripheral blood. This work is supported by T32HL105324 to AMS. This is the full abstract presented at the American Physiology Summit 2024 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.

ARE THERE NON-RESPONDERS TO HIIT IN CANCER SURVIVORS? CHANGES IN CARDIORESPIRATORY FITNESS, BODY COMPOSITION AND SYSTEMIC INFLAMMATION

INTRODUCTION High intensity interval training (HIIT) has been shown to elicit significant improvements in VO2peak in cancer survivors. Only 46-60% of healthy individuals are reported to respond to exercise interventions, though this rate has not been investigated in cancer survivors. AIMS: To determine the response rate in cancer survivors over 28-weeks of HIIT as measured by changes in cardiorespiratory fitness. Secondarily, the study aimed to observe associations between changes in cardiorespiratory fitness, body composition and inflammatory markers. METHODS 131 survivors of breast, prostate or colorectal cancer were observed over 28-weeks of HIIT (4x4 minutes; 85-95% HRpeak). VO2peak, body composition and markers of systemic inflammation were assessed at baseline, four-, 16- and 28-weeks. An improvement in VO2peak of 3.5 ml.kg-1.min-1 was used as a standard of minimal clinically important difference (MCID). Body composition was measured using DEXA, and inflammatory markers were assessed for each timepoint. RESULTS 59.6% of participants improved their VO2peak greater than MCID (+3.5 ml.kg-1.min-1) and these individuals were retrospectively classified as responders. Responders showed improvements in VO2peak at four- and 16-weeks and maintained this change through to 28-weeks (0-4 weeks: +2.92 ml.kg-1.min-1, p&amp;lt;0.001; 0-16 weeks: +5.70 ml.kg-1.min-1, p&amp;lt;0.001; and 0-28 weeks: +5.30 ml.kg-1.min-1, p&amp;lt;0.001). No significant change in VO2peak was seen in non-responders (40.4%). Time since treatment, cancer type, and cancer treatment were all found to contribute to a model predicting VO2peak change (R=0.464, R2 = 21.5%., adj R2=16.1%, p&amp;lt;0.001). Body composition and inflammatory markers improved in response to training however were not associated with VO2peak change. CONCLUSIONS HIIT elicited a MCID in VO2peak in almost 60% of cancer survivors. Independent to VO2peak change and cancer type, survivors showed significant favourable changes in inflammation and body composition in response to training.

Paclitaxel-Associated Mechanical Sensitivity and Neuroinflammation Are Sex-, Time-, and Site-Specific and Prevented through Cannabigerol Administration in C57Bl/6 Mice.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most prevalent and dose-limiting complications in chemotherapy patients. One identified mechanism underlying CIPN is neuroinflammation. Most of this research has been conducted in only male or female rodent models, making direct comparisons regarding the role of sex differences in the neuroimmune underpinnings of CIPN limited. Moreover, most measurements have focused on the dorsal root ganglia (DRG) and/or spinal cord, while relatively few studies have been aimed at characterizing neuroinflammation in the brain, for example the periaqueductal grey (PAG). The overall goals of the present study were to determine (1) paclitaxel-associated changes in markers of inflammation in the PAG and DRG in male and female C57Bl6 mice and (2) determine the effect of prophylactic administration of an anti-inflammatory cannabinoid, cannabigerol (CBG). In Experiment 1, male and female mice were treated with paclitaxel (8-32 mg/kg/injection, Days 1, 3, 5, and 7) and mechanical sensitivity was measured using Von Frey filaments on Day 7 (Cohort 1) and Day 14 (Cohort 2). Cohorts were euthanized on Day 8 or 15, respectively, and DRG and PAG were harvested for qPCR analysis of the gene expression of markers of pain and inflammation Aig1, Gfap, Ccl2, Cxcl9, Tlr4, Il6, and Calca. In Experiment 2, male and female mice were treated with vehicle or 10 mg/kg CBG i.p. 30 min prior to each paclitaxel injection. Mechanical sensitivity was measured on Day 14. Mice were euthanized on Day 15, and PAG were harvested for qPCR analysis of the gene expression of Aig1, Gfap, Ccl2, Cxcl9, Tlr4, Il6, and Calca. Paclitaxel produced a transient increase in potency to produce mechanical sensitivity in male versus female mice. Regarding neuroinflammation, more gene expression changes were apparent earlier in the DRG and at a later time point in the PAG. Also, more changes were observed in females in the PAG than males. Overall, sex differences were observed for most markers at both time points and regions. Importantly, in both the DRG and PAG, most increases in markers of neuroinflammation and pain occurred at paclitaxel doses higher than those associated with significant changes in the mechanical threshold. Two analytes that demonstrated the most compelling sexual dimorphism and that changed more in males were Cxcl9 and Ccl2, and Tlr4 in females. Lastly, prophylactic administration of CBG protected the male and female mice from increased mechanical sensitivity and female mice from neuroinflammation in the PAG. Future studies are warranted to explore how these sex differences may shed light on the mechanisms of CIPN and how non-psychoactive cannabinoids such as CBG may engage these targets to prevent or attenuate the effects of paclitaxel and other chemotherapeutic agents on the nervous system.

Short-term immunotoxicity induced by florpyrauxifen-benzyl herbicide exposure in the spleen of male albino mice.

Florpyrauxifen-benzyl (FPB)is a new arylpicolinate systemic herbicide that has been used to control or suppress the majority of herbicide-resistant biotype weeds in rice. To our knowledge, the impact of FPB on the immune system remains undetected thus far. Hence, this work aimed to address the toxic effects of FPB and the possible related mechanisms on the spleen of exposed mice. Initially, an acute toxicological test was performed to ascertain the median lethal dose (LD50) of FPB for 24 h which was found to be 371.54 mg/kg b.wt. For mechanistic evaluation of FPB toxicity, three sublethal doses (1/20th, 1/10th, and 1/5thLD50) were orally administered to mice for 21 consecutive days. Changes in spleen relative weight, oxidative status, apoptotic and inflammatory markers, histopathological alterations were evaluated. Following the FPB exposure, significant (p < 0.05) decline in spleen index, apoptotic features, histolopathological changes were observed. Additionally, excessive oxidative stress in spleen tissues was monitored by downregulating antioxidant enzymes and upregulating the oxidant parameters. Furthermore, exposure to FPB resulted in notable activation of the NF-қB signaling pathway, accompanied by elevated levels of pro-inflammatory cytokines (namely, IL-1βand TNF-α)as well as CD3 and CD19 levels have decreased significantly in spleen tissues. Collectively, FPB exposure exhibited apoptosis, oxidative stress, immunosuppression, and inflammatory response in a dose-dependent manner, leading to spleen tissue damage and immunotoxicity. Further studies on FPB is recommended to outstand its hazards on ecosystems.

Changes in clinical parameters and inflammatory markers after blood culture collection facilitate early identification of positive culture in adult patients with COVID-19 and clinically suspected bloodstream infection.

We explored whether changes in clinical parameters and inflammatory markers can facilitate early identification of positive blood culture in adult patients with COVID-19 and clinically suspected bloodstream infection (BSI). This single-center retrospective study enrolled 20 adult patients with COVID-19 admitted to the intensive care unit who underwent blood culture for clinically suspected BSI (February 2020-November 2021). We divided patients into positive (Pos) and negative blood culture groups. Clinical parameters and inflammatory markers were obtained from medical records between blood culture collection and the first positive or negative result and compared between groups on different days. Patients in the positive culture group had significantly older age and higher D-dimer, immunoglobulin 6 (IL-6), and Sequential Organ Failure Assessment score as well as lower albumin (ALB). The area under the receiver operating characteristic curve (AUC) was 0.865 for IL-6, D-dimer and ALB on the first day after blood culture collection; the AUC was 0.979 for IL-6, IL-10, D-dimer, and C-reactive protein on the second day after blood culture collection. Changes in clinical parameters and inflammatory markers after blood culture collection may facilitate early identification of positive culture in adult patients with COVID-19 and clinically suspected BSI.

Head-to-head comparison of multi-dose oritavancin and dalbavancin for complicated infections: A propensity score-matched analysis

BackgroundOritavancin and dalbavancin are long-acting lipoglycopeptide antibiotics approved for the treatment of skin and skin structure infections. Recently, they have been used for outpatient antimicrobial therapy for complicated infections. No head-to-head studies exist for this purpose. ObjectiveTo compare outcomes of patients treated with multiple doses of oritavancin or dalbavancin for complicated infections. Patients and MethodsThis was a single-centre, retrospective cohort study evaluating adult patients who received two or more doses of lipoglycopeptides for complicated infections from February 2019 through December 2022. Patients receiving oritavancin were compared to dalbavancin after propensity score-matching. The primary endpoint was clinical success at 90 days. Other endpoints included: 30-day re-admission, 30-day mortality, adverse drug reactions (ADRs), and changes in white blood cell count and inflammatory markers after the first dose. ResultsAfter exclusions and propensity score-matching, 131 matched pairs (N = 262) were included in the analysis. Most patients were receiving lipoglycopeptide therapy for osteomyelitis. There was no significant difference in clinical success at 90 days in patients who received oritavancin compared to those who received dalbavancin (99 [76%] vs. 103 [79%], respectively; P = 0.556). There was no significant difference in secondary endpoints, however, there was a trend towards higher incidence of ADRs oritavancin compared to dalbavancin (9 [7%] vs. 2 [2%], respectively; P = 0.060) which led to more treatment discontinuation. ConclusionThere was no significant difference in efficacy between multi-dose oritavancin and dalbavancin for the treatment of complicated infections. Both agents were generally well tolerated; however, dalbavancin may be better tolerated when long-term treatment is warranted.

Obesogenic Diet in Mice Leads to Inflammation and Oxidative Stress in the Mother in Association with Sex-Specific Changes in Fetal Development, Inflammatory Markers and Placental Transcriptome.

Obesity during pregnancy is related to adverse maternal and neonatal outcomes. Factors involved in these outcomes may include increased maternal insulin resistance, inflammation, oxidative stress, and nutrient mishandling. The placenta is the primary determinant of fetal outcomes, and its function can be impacted by maternal obesity. The aim of this study on mice was to determine the effect of obesity on maternal lipid handling, inflammatory and redox state, and placental oxidative stress, inflammatory signaling, and gene expression relative to female and male fetal growth. Female mice were fed control or obesogenic high-fat/high-sugar diet (HFHS) from 9 weeks prior to, and during, pregnancy. On day 18.5 of pregnancy, maternal plasma, and liver, placenta, and fetal serum were collected to examine the immune and redox states. The placental labyrinth zone (Lz) was dissected for RNA-sequencing analysis of gene expression changes. the HFHS diet induced, in the dams, hepatic steatosis, oxidative stress (reduced catalase, elevated protein oxidation) and the activation of pro-inflammatory pathways (p38-MAPK), along with imbalanced circulating cytokine concentrations (increased IL-6 and decreased IL-5 and IL-17A). HFHS fetuses were asymmetrically growth-restricted, showing sex-specific changes in circulating cytokines (GM-CSF, TNF-α, IL-6 and IFN-γ). The morphology of the placenta Lz was modified by an HFHS diet, in association with sex-specific alterations in the expression of genes and proteins implicated in oxidative stress, inflammation, and stress signaling. Placental gene expression changes were comparable to that seen in models of intrauterine inflammation and were related to a transcriptional network involving transcription factors, LYL1 and PLAG1. This study shows that fetal growth restriction with maternal obesity is related to elevated oxidative stress, inflammatory pathways, and sex-specific placental changes. Our data are important, given the marked consequences and the rising rates of obesity worldwide.

Abstract P298: Cross-Sectional and Longitudinal Associations Between Fast Food Outlet Access and Inflammatory Markers in the US-Based Nurses’ Health Study II

Background: Access to fast food outlets (FFO) has increased in recent years and may decrease diet quality and increase cardiovascular disease risk. Inflammation is a well-established cardiovascular disease risk factor, but it remains unclear whether inflammation is one of the pathways explaining associations between the food environment and inflammatory markers. Methods: We included 6,609 participants from the US-based Nurses’ Health Study II (NHS-II), a prospective cohort of registered female nurses. Counts of FFO were obtained from the Infogroup US Historical Business Data within 1500-meter circular buffers and assigned to participants’ residential addresses from 1998 to 2011. Biomarkers included C-reactive protein (CRP), Interleukin-6 (IL-6), Tumor necrosis factor α receptor 2 (TNFαR2, in a subset), and adiponectin. We evaluated cross-sectional associations between counts of FFO (1998) and inflammatory markers (1999) in linear regression models and evaluated longitudinal associations by the change in counts of FFO between 1998 and 2010 and the change in inflammatory markers between 1999 and 2011 using linear mixed models. Models were adjusted for age, race/ethnicity, partners’ education level, smoking, neighborhood socioeconomic status, and population density. Interaction terms were included to explore effect modification by baseline neighborhood socioeconomic status and population density. Results: Our study comprised women with a mean age of 45.3 (+/- 4.4) years at 1998. A one-unit higher count of FFO within a 1500m buffer was not cross-sectionally associated with CRP (β: 0.004, 95%CI: -0.004, 0.010), IL-6 (β: 0.001, 95%CI: -0.001, 0.004), TNFR2 (β: 0.051, 95%CI: -1.495, 1.597), or adiponectin (β: -6.054, 95%CI: -14.576, 2.468). No associations were found in longitudinal models (CRP (β: 0.000, 95%CI: -0.007, 0.008), IL-6 (β: 0.001, 95%CI: -0.002, 0.003), or adiponectin (β: -1.127, 95%CI: -11.889, 14.3152)). No significant effect modification was found between count of FFO and neighborhood socioeconomic status, or population density (P-for-interaction &gt;0.1). Conclusions: While several previous studies have found an association between frequency of consumption of food at fast food restaurants and biomarkers of cardiovascular risk, at the community level, we did not find associations between the count of FFO and several inflammatory markers in a population of US female nurses.

The long-term effect of periodontitis treatment on changes in blood inflammatory markers in patients with generalized aggressive periodontitis.

Periodontitis is characterized by local inflammatory conditions in the periodontium, its severe form has been associated with elevated systemic inflammatory markers. However, the long-term effects of periodontal inflammation control on systemic inflammatory markers are unclear. This study aimed to investigate the long-term effects of periodontal therapy on the levels of peripheral venous blood inflammatory markers in patients with generalized aggressive periodontitis (GAgP), all of whom were now diagnosed as Stage III or IV Grade C periodontitis. Patients with GAgP were consecutively recruited from April 2013 to August 2014 (T0). Active periodontal treatment (APT) was provided, and follow-ups were conducted over a 3- to 5-year period (T1). Clinical parameters were assessed and fasting venous blood was collected at T0 and T1. Complete blood cell counts were obtained, and biochemical analyses were performed to evaluate the levels of serum components. The correlations between probing depth (PD) and hematological parameters were analyzed. A total of 49 patients with GAgP completed APT and follow-ups. Probing depth (PD) reduced from 5.10 ± 1.07 mm at T0 to 3.15 ± 0.65 mm at T1. For every 1-mm reduction in PD after treatment, the neutrophil count, neutrophil-lymphocyte ratio, and total protein concentration were reduced by 0.33 × 109 /L, 0.26, and 1.18 g/L, respectively. In contrast, the albumin/globulin ratio increased by 0.10. This study indicated that periodontal therapy may have beneficial effects on peripheral venous blood inflammatory markers in patients with GAgP during long-term observation.

Intravenous MSC-Treatment Improves Impaired Brain Functions in the R6/2 Mouse Model of Huntington's Disease via Recovered Hepatic Pathological Changes.

Huntington's disease (HD), a congenital neurodegenerative disorder, extends its pathological damages beyond the nervous system. The systematic manifestation of HD has been extensively described in numerous studies, including dysfunction in peripheral organs and peripheral inflammation. Gut dysbiosis and the gut-liver-brain axis have garnered greater emphasis in neurodegenerative research, and increased plasma levels of pro-inflammatory cytokines have been identified in HD patients and various in vivo models, correlating with disease progression. In the present study, we investigated hepatic pathological markers in the liver of R6/2 mice which convey exon 1 of the human mutant huntingtin gene. Furthermore, we evaluated the impact of intravenously administered Mesenchymal Stromal Cells (MSCs) on the liver enzymes, changes in hepatic inflammatory markers, as well as brain pathology and behavioral deficits in R6/2 mice. Our results revealed altered enzyme expression and increased levels of inflammatory mediators in the liver of R6/2 mice, which were significantly attenuated in the MSC-treated R6/2 mice. Remarkably, neuronal pathology and altered motor activities in the MSC-treated R6/2 mice were significantly ameliorated, despite the absence of MSCs in the postmortem brain. Our data highlight the importance of hepatic pathological changes in HD, providing a potential therapeutic approach. Moreover, the data open new perspectives for the search in blood biomarkers correlating with liver pathology in HD.

The role and mechanism of PDZ binding kinase in hypobaric and hypoxic acute lung injury.

Acute lung injury (ALI) caused by hypobaric hypoxia (HH) is frequently observed in high-altitude areas, and it is one of the leading causes of death in high-altitude-related diseases due to its rapid onset and progression. However, the pathogenesis of HH-related ALI (HHALI) remains unclear, and effective treatment approaches are currently lacking. A new mouse model of HHALI developed by our laboratory was used as the study subject (Chinese patent No. ZL 2021 1 1517241 X). Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the messenger RNA (mRNA) expression levels of PDZ-binding kinase (PBK), sirtuin 1 (SIRT1), and PTEN-induced kinase 1 (PINK1) in mouse lung tissue. Hematoxylin and eosin staining was used to observe the main types of damage and damaged cells in lung tissue, and the lung injury score was used for quantification. The wet-dry (W/D) ratio was used to measure lung water content. Enzyme-linked immunosorbent assay was used to detect changes in inflammatory factors and oxidative stress markers in the lungs. Western blotting verified the expression of various mitochondrial autophagy-related proteins. The 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimi-dazoylcarbocyanine iodide (JC-1) method was used determined the health status of mitochondria based on changes in mitochondrial membrane potential. Transmission electron microscopy was used to directly observe the morphology of mitochondria. Multicolor immunofluorescence was used to observe the levels of mitochondrial autophagy markers. Other signaling pathways and molecular mechanisms that may play a role in epithelial cells were analyzed via through RNA sequencing. Low pressure and hypoxia caused pathological changes in mouse lung tissue, mainly ALI, leading to increased levels of inflammatory factors and intensified oxidative stress response in the lungs. Overexpression of PBK was found to alleviate HHALI, and activation of the p53 protein was shown to abrogate this therapeutic effect, while activation of SIRT1 protein reactivated this therapeutic effect. The therapeutic effect of PBK on HHALI is achieved via the activation of mitochondrial autophagy. Finally, RNA sequencing demonstrated that besides mitochondrial autophagy, PBK also exerts other functions in HHALI. Overexpression of PBK inhibits the expression of p53 and activates SIRT1-PINK1 axis mediated mitochondrial autophagy to alleviate HHALI.

Integrated exercise program in opioid agonist therapy clinics and effect on psychological distress: study protocol for a randomized controlled trial (BAReAktiv)

BackgroundSubstance use disorder is associated with unhealthy lifestyle choices, resulting in adverse social and health consequences. People with opioid use disorder receiving opioid agonist therapy, in particular, have high morbidity and reduced quality of life. Physical activity is recommended as an adjunctive treatment for people with substance use disorder, but there is minimal evidence from randomized controlled trials on the effects of this among people with substance use disorder receiving opioid agonist therapy.MethodsBAReAktiv is a multicentre randomized controlled trial. The study aims to recruit 324 patients receiving opioid agonist therapy (parallel groups randomized 1:1 to integrated exercise intervention or control, superiority trial). A 16-week group-based integrated exercise intervention with workouts twice a week. The exercise program consists of endurance and resistance training. The target group will be patients 18 years and older receiving opioid agonist therapy in outpatient clinics in several centers in Western Norway. The primary outcome of the study is the effect on psychological distress measured by Hopkins’ symptom checklist with ten items. Secondary outcome measures include physical functioning assessed with a 4-min step test, activity level, fatigue symptoms, quality of life, and changes in inflammation markers. This study will provide improved knowledge on the effects of an integrated exercise program in opioid agonist therapy.DiscussionSystematically integrating exercise programs for people receiving opioid agonist therapy could lead to a shift towards a stronger focus on health behaviors in outpatient care. Integrating exercise could benefit patient recovery and reduce disease burden. Further scale-up will be considered if the provided exercise program is safe and effective.Trial registrationClinicalTrials.gov. NCT05242848. Registered on February 16, 2022.

Ablative fractional CO2 laser treatment promotes wound healing phenotype in skin macrophages.

Ablative fractional laser (AFL) treatment is a well-established method for reducing signs of skin photoaging. However, the biological mechanisms underlying AFL-induced healing responses and skin rejuvenation remain largely unknown. It is known that macrophages play an important role in orchestrating healing, normalization, and remodeling processes in skin. Macrophage phenotypes are characterized by inflammatory markers, including arginase-1 (Arg1), major histocompatibility class II molecules (MHC II), and CD206. This study aims to explore AFL's effect on macrophage phenotype by evaluating changes in inflammatory markers and the potential concurrent accumulation of Arg1 in the skin. Mice (n = 9) received a single AFL treatment on the left side of the back skin (100 mJ/microbeam, 5% density) while the right side of the back remained untreated as control. Treated and untreated skin from each mouse were collected Day 5 posttreatment for flow cytometry and histology analysis. Flow cytometry evaluated the immune infiltration of macrophages and the expression of macrophage inflammatory markers (Arg1, MHC II, and CD206). In addition, Arg1 presence in the skin was evaluated through antibody staining of histology samples and quantification was performed using QuPath image analysis software. Following AFL, the number of macrophages increased 11-fold (p = 0.0053). Phenotype analysis of AFL-treated skin revealed an increase in the percentage of macrophages positive for Arg1 (p < 0.0001) and a decrease in the percentage of macrophages positive for MHC II (p < 0.0001) compared to untreated skin. No significant differences were observed in percentage of CD206-positive macrophages (p = 0.8952). Visualization of AFL-treated skin demonstrated a distinct pattern of Arg1 accumulation that correlated with the microscopic treatment zones (MTZ). Quantification of the percentage of Arg1-positive area in epidermis and dermis showed a significant increase from 3.5% ± 1.2% to 5.2% ± 1.7 (p = 0.0232) and an increase from 2.2% ± 1.2% to 9.6% ± 3.3 (p < 0.0001) in whole skin samples. AFL treatment polarizes macrophages toward a wound healing phenotype and induces Arg1 accumulation in the MTZ. We propose that the polarized wound healing macrophages are a major source for the increased Arg1 levels observed in the skin following treatment.

Trajectories of neutrophil-to-lymphocyte ratios during neoadjuvant chemotherapy correlate with short- and long-term outcomes in gastric cancer: a group-based trajectory analysis

BackgroundSystemic inflammatory factors can predict the survival prognosis of gastric cancer (GC) patients after neoadjuvant chemotherapy (NACT). However, whether longitudinal changes in systemic inflammatory factors are associated with short - and long-term outcomes has not been reported.MethodsThis study is a retrospective analysis of 216 patients with advanced gastric cancer who received NACT between January 2011 and June 2019, comparing receiver operating characteristic (ROC) curves for screening suitable inflammatory markers. Group-based trajectory modeling (GBTM) was used to analyze longitudinal changes in inflammatory markers during NACT to identify different potential subgroups and to compare postoperative complications, recurrence-free survival (RFS), and overall survival (OS) among subgroups.ResultsUltimately, neutrophil-lymphocyte ratio (NLR) had the highest area under the curve (AUC) value in predicting prognosis was included in the GBTM analysis. Three trajectories of NLR were obtained: Stable group (SG) (n = 89), Ascent-descend group (ADG) (n = 80) and Continuous descend group (CDG) (n = 47). Compared with SG, ADG and CDG are associated with an increased risk of postoperative recurrence and death. The median time of RFS and OS of SG was longer than that of ADG and CDG (median RFS 81 vs. 44 and 22 months; median OS 69 vs. 41 and 30 months). In addition, CDG had significantly higher postoperative serious complications than SG and ADG (17 (36.2%) vs. 17 (19.1%) and 12 (15.0%); p = 0.005).ConclusionThere were different trajectories of NLR during NACT, and these potential trajectories were significantly associated with severe postoperative complications, recurrence, and mortality in patients with GC.

The effect of Oenothera biennis (Evening primrose) oil on inflammatory diseases: a systematic review of clinical trials

BackgroundEvening primrose oil (EPO), extracted from the seeds of Oenothera biennis, has gained attention for its therapeutic effects in various inflammatory conditions.MethodWe performed a systematic search in multiple databases and defined the inclusion criteria based on the following PICOs: P: Patients with a form of inflammatory condition, I: EPO, C: Placebo or other therapeutic interventions, O: changes in inflammatory markers or patients’ symptoms; S: randomized controlled trials. The quality of the RCTs was evaluated using Cochrane’s RoB tool.ResultsSeveral conditions were investigated in the literature. In rheumatoid arthritis, mixed results were observed, with some studies reporting significant improvements in symptoms while others found no significant impact. EPO showed some results in diabetes mellitus, atopic eczema, menopausal hot flashes, and mastalgia. However, it did not demonstrate effectiveness in chronic hand dermatitis, tardive dyskinesia, psoriatic arthritis, cystic fibrosis, hepatitis B, premenstrual syndrome, contact lens-associated dry eyes, acne vulgaris, breast cyst, pre-eclampsia, psoriasis, or primary Sjogren's syndrome. Some results were reported from multiple sclerosis after EPO consumption. Studies in healthy volunteers indicated no significant effect of EPO on epidermal atrophy, nevertheless, positive effects on the skin regarding hydration and barrier function were achieved.ConclusionSome evidence regarding the potential benefits of EPO in inflammatory disorders were reported however caution is due to the limitations of the current survey. Overall, contemporary literature is highly heterogeneous and fails to provide strong recommendations regarding the efficacy of EPO on inflammatory disorders. Further high-quality studies are necessitated to draw more definite conclusions and establish O. biennis oil effectiveness as an assuring treatment option in alleviating inflammatory conditions.