Including Interleukin Research Articles

Correlation between the Degree of Inflammation and Stress Indicators and Concurrent Cognitive Impairment in Patients with Severe Craniocerebral Injury.

Craniocerebral injuries can cause inflammation and oxidative stress, and can have permanent effects on cognitive function. Moreover, over time, excessive expression of inflammatory factors and high levels of oxidative stress will be detrimental to recovery from craniocerebral injury and may exacerbate neurological damage, further damaging neurons and other cellular structures. In this study, we investigated changes in inflammation and stress indicators in patients with severe craniocerebral injuries, and analyzed associations with concurrent cognitive impairment. 82 patients with severe craniocerebral injuries admitted to Longyou County People's Hospital during January 2022-June 2023 were selected for retrospective study. Levels of inflammatory factors and the degree of oxidative stress were recorded and compared between the acute and chronic phases. Inflammatory measures included interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α) and C-reactive protein (CRP), and oxidative stress indicators included human cortisol (Cor), norepinephrine (NE), and superoxide dismutase (SOD). The patients' cognitive function was evaluated using the Mini-Mental State Examination (MMSE), and the incidence of cognitive impairment was assessed. Spearman's correlation was used to analyze associations between inflammatory and oxidative stress measures and MMSE scores; logistic regression was used to analyze the related factors affecting the patients' concurrent cognitive impairment; and the receiver operating characteristic (ROC) curve was used to test the predictive value of inflammatory and oxidative stress measures on the patients' concurrent cognitive impairment in the acute phase and the chronic phase. Patients had higher levels of IL-6, IL-10, TNF-α, CRP, Cor, and NE, and lower levels of SOD, in the acute phase compared to the chronic phase (p < 0.05). MMSE scores were higher in the acute phase than in the chronic phase (p < 0.05). A total of 50 cases were complicated by cognitive impairment, and the incidence of cognitive impairment was 60.98%. The levels of IL-6, IL-10, TNF-α, CRP, Cor, and NE in the chronic phase were positively correlated with the concurrent cognitive impairment, and the level of SOD was negatively correlated with the concurrent cognitive impairment (p < 0.05). Single-factor analysis showed that age and levels of IL-6, IL-10, TNF-α, CRP, Cor, and NE were higher in the cognitively impaired group than in the cognitively normal group, SOD levels were lower than in the cognitively normal group, and percentages of below-secondary school and frontal lobe damage were higher than those in the cognitively normal group (p < 0.05). Logistic regression analysis showed that below-secondary school, frontal lobe injury, higher levels of IL-6, IL-10, TNF-α, and CRP in the chronic phase, and lower levels of SOD in the chronic phase were all relevant factors affecting the patients' concurrent cognitive impairment. As shown by the ROC curve, the area under the curve (AUC) for the combination of indicators was 0.949, sensitivity was 0.980, and specificity was 0.844. The incidence of cognitive impairment is higher in patients with severe craniocerebral injury, and the levels of inflammation and oxidative stress, which are not conducive to recovery, are higher in patients in the acute stage. The risk of concurrent cognitive impairment is higher in patients with a lower level of literacy, frontal lobe injury, and high levels of inflammatory factors and oxidative stress in the chronic stage; these indicators, therefore, have a significant predictive effect on the prognosis of the patients.

Bear Bile Powder Ameliorates LPS-Induced Acute Lung Injury by Inhibiting CD14 Pathway and Improving Intestinal Flora: Exploration of "Fei (Lung)-Dachang (Large Intestine) Interaction".

To explore the effect of bear bile powder (BBP) on acute lung injury (ALI) and the underlying mechanism. The chemical constituents of BBP were analyzed by ultra-high-pressure liquid chromatography-mass spectrometry (UPLC-MS). After 7 days of adaptive feeding, 50 mice were randomly divided into 5 groups by a random number table (n=10): normal control (NC), lipopolysaccharide (LPS), dexamethasone (Dex), low-, and high-dose BBP groups. The dosing cycle was 9 days. On the 12th and 14th days, 20 µL of Staphylococcus aureus solution (bacterial concentration of 1 × 10-7 CFU/mL) was given by nasal drip after 1 h of intragastric administration, and the mice in the NC group was given the same dose of phosphated buffered saline (PBS) solution. On the 16th day, after 1 h intragastric administration, 100 µL of LPS solution (1 mg/mL) was given by tracheal intubation, and the same dose of PBS solution was given to the NC group. Lung tissue was obtained to measure the myeloperoxidase (MPO) activity, the lung wet/dry weight ratio and expressions of CD14 and other related proteins. The lower lobe of the right lung was obtained for pathological examination. The concentrations of inflammatory cytokines including interleukin (IL)-6, tumour necrosis factor α (TNF-α ) and IL-1β in the bronchoalveolar lavage fluid (BALF) were detected by enzyme linked immunosorbent assay, and the number of neutrophils was counted. The colonic contents of the mice were analyzed by 16 sRNA technique and the contents of short-chain fatty acids (SCFAs) were measured by gas chromatograph-mass spectrometer (GC-MS). UPLC-MS revealed that the chemical components of BBP samples were mainly tauroursodeoxycholic acid and taurochenodeoxycholic acid sodium salt. BBP reduced the activity of MPO, concentrations of inflammatory cytokines, and inhibited the expression of CD14 protein, thus suppressing the activation of NF-κB pathway (P<0.05). The lung histopathological results indicated that BBP significantly reduced the degree of neutrophil infiltration, cell shedding, necrosis, and alveolar cavity depression. Moreover, BBP effectively regulated the composition of the intestinal microflora and increased the production of SCFAs, which contributed to its treatment effect (P<0.05). BBP alleviates lung injury in ALI mouse through inhibiting activation of NF-κB pathway and decreasing expression of CD14 protein. BBP may promote recovery of ALI by improving the structure of intestinal flora and enhancing metabolic function of intestinal flora.

Application of 3D printing surgical training models in the preoperative assessment of robot-assisted partial nephrectomy

BackgroundTo explore the application effect of 3D printing surgical training models in the preoperative assessment of robot-assisted partial nephrectomy.MethodsEighty patients who underwent robot-assisted partial nephrectomy surgery between January 2022 and December 2023 were selected and divided into two groups according to the chronological order. The control group (n = 40) received preoperative assessment with verbal and video education from January 2022 to December 2022, while the observation group (n = 40) received preoperative assessment with 3D printing surgical training models combined with verbal and video education from January 2023 to December 2023. The preoperative anxiety, information demand score, and surgical awareness were compared between the two groups. The physiological stress indicators, including interleukin-6 (IL-6), angiotensin II (AT II), adrenocorticotropic hormone (ACTH), cortisol (Cor), mean arterial pressure (MAP), and heart rate (HR), were also measured at different time points before and after surgery.They were 6:00 am on the day before surgery (T0), 6:00 am on the day of the operation (T1), 6:00 am on the first day after the operation (T2), and 6:00 am on the third day after the operation (T3).The preparation rate before surgery was compared between the two groups.ResultsThe anxiety and surgical information demand scores were lower in the observation group than in the control group before anesthesia induction, and the difference was statistically significant (P < 0.001). Both groups had lower scores before anesthesia induction than before preoperative assessment, and the difference was statistically significant (P < 0.05). The physiological stress indicators at T1 time points were lower in the observation group than in the control group, and the difference was statistically significant (P < 0.05). The overall means of the physiological stress indicators differed significantly between the two groups (P < 0.001). Compared with the T0 time point, the T1, T2, and T3 time points in both groups were significantly lower, and the difference was statistically significant (P < 0.05). The surgical awareness and preparation rate before surgery were higher in the observation group than in the control group, and the difference was statistically significant (P < 0.05).ConclusionThe preoperative assessment mode using 3D printing surgical training models combined with verbal and video education can effectively reduce the psychological and physiological stress responses of surgical patients, improve their surgical awareness, and enhance the preparation rate before surgery.

In-silico analysis of ribosome inactivating protein (RIP) of the Cucurbitaceae family.

Ribosome-inactivating proteins (RIPs) are highly active N-glycosidases that depurinate both bacterial and eukaryotic rRNAs, halting protein synthesis during translation. Found in a diverse spectrum of plant species and tissues, RIPs possess antifungal, antibacterial, antiviral, and insecticidal properties linked to plant defense. In this study, we investigated the physiochemical properties of RIP peptides from the Cucurbitaceae family through bioinformatics approaches. Molecular weight, isoelectric point, aliphatic index, extinction coefficient, and secondary structures were analyzed, revealing their hydrophobic nature. The novelty of this work lies in the comprehensive examination of RIPs from the Cucurbitaceae family and their potential therapeutic applications. The study also elucidated the binding interactions of Cucurbitaceae RIPs with key biological targets, including Interleukin-6 (IL-6). Strong hydrogen bond interactions between RIPs and these targets suggest potential for innovative insilico drug design and therapeutic applications, particularly in cancer treatment. Comprehensive analysis of bond lengths using Ligpolt + software provides insights for optimizing molecular interactions, offering a valuable tool for drug design and structural biology studies.

Celastrus orbiculatus Extract Inhibits Immune Inflammatory Thrombotic State of B-Lymphoma.

To investigate the inhibitory effect of Celastrus orbiculatus extracts (COE) on the proliferation of lymphoma cells and the immune regulation ability on inflammation and thrombophilia in vivo. The 38B9 lymphoma cells were treated with COE (160 µ g/mL) and CTX (25 µ mol/L). The apoptosis rate and cell cycle of each group were detected by flow cytometry. The secretion of inflammatory factors, including interleukin (IL)-6, IL-10, and tumor necrosis factor α (TNF-α), in cell supernatant was detected by enzyme-linked immunosorbent assay (ELISA). In vivo, BALB/c mice were subcutaneously injected with 38B9 lymphoma cells to establish lymphoma model. COE (3 mg·kg-1·d-1) and CTX (40 mg·kg-1·d-1) were administered to the model mice, respectively. The expression of plasma inflammatory factors (IL-6, IL-10 and TNF-α) and thrombus indexes, including D-dimer (D-D), von Willebrand factor (vWF) and tissue factor (TF), were detected by ELISA before tumor bearing (1 d), after tumor formation (14 d) and after intervention (21 d). PicoGreen dsDNA was used to detect the level of serum neutrophil extracellular traps (NETs). Flow cytometry was used to detect the expression of platelet activation marker calcium-dependent lectin-like receptor 2 (CLEC-2). The tumor growth and survival of mice were recorded. The 38B9 lymphoma cells were apoptotic after the intervention of COE and CTX. The ratio of G2-M phase cells decreased in COE intervented cells compared with the control cells (P<0.05), and S phase cells decreased in CTX intervented cells (P<0.05). Also, the secretion level of IL-6 was significantly reduced after COE or CTX intervention (P<0.05), and IL-10 was significantly increased (P<0.05). Furthermore, the tumor mass was reduced, and the median survival time was longer in COE and CTX intervented tumor-bearing mice than in non-intervented mice. The significantly lower levels of TNF-α, IL-6, NETs, TF, DD and CLEC-2, as well as higher IL-10 were observed in COE and CTX treatment mice in comparision with the control mice (P<0.05). COE has a mild and stable anti-tumor effect, which can reduce the secretion of inflammatory factors by lymphoma cells and regulate thrombophilic state caused by tumor inflammatory microenvironment.

Interleukin-1β moderates the relationships between middle frontal-mACC/insular connectivity and depressive symptoms in bipolar II depression

The functional alterations of the brain in bipolar II depression (BDII-D) and their clinical and inflammatory associations are understudied. We aim to investigate the functional brain alterations in BDII-D and their relationships with inflammation, childhood adversity, and psychiatric symptoms, and to examine the moderating effects among these factors. Using z-normalized amplitude of low-frequency fluctuation (zALFF), we assessed the whole-brain resting-state functional activity between 147 BDII-D individuals and 150 healthy controls (HCs). Differential ALFF regions were selected as seeds for functional connectivity analysis to observe brain connectivity alterations resulting from abnormal regional activity. Four inflammatory cytokines including interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) and five clinical scales including Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), Positive and Negative Syndrome Scale (PANSS), Columbia-Suicide Severity Rating Scale (C-SSRS), and Childhood Trauma Questionnaire (CTQ) were tested and assessed in BDII-D. Partial correlations with multiple comparison corrections identified relationships between brain function and inflammation, childhood adversity, and psychiatric symptoms. Moderation analysis was conducted based on correlation results and previous findings. Compared to HCs, BDII-D individuals displayed significantly lower zALFF in the superior and middle frontal gyri (SFG and MFG) and insula, but higher zALFF in the occipital-temporal area. Only the MFG and insula-related connectivity exhibited significant differences between groups. Within BDII-D, lower right insula zALFF value correlated with higher IL-6, CRP, and emotional adversity scores, while lower right MFG zALFF was related to higher CRP and physical abuse scores. Higher right MFG-mid-anterior cingulate cortex (mACC) connectivity was associated with higher IL-1β. Moreover, IL-1β moderated associations between higher right MFG-mACC/insula connectivity and greater depressive symptoms. This study reveals that abnormal functional alterations in the right MFG and right insula were associated with elevated inflammation, childhood adversity, and depressive symptoms in BDII-D. IL-1β may moderate the relationship between MFG-related connectivity and depressive symptoms.

Calycosin action against atherosclerosis: integrating network pharmacology and in-silico investigation

Atherosclerosis, caused by lipid deposit in the arterial wall for narrowing the arteries, is an increased risk factor of developing heart failure. Presently, clinical first-line drug therapy can be found with side effects, and thus new substitute medication should be developed needfully. Calycosin is one of the most bioactive products refined from natural plant, and it exerts promising cardiovascular protective effect. However, the pharmacological mechanisms of calycosin against atherosclerosis have not been elaborated. In this study, a systematic network pharmacology combined with molecular docking analysis was used to reveal the interaction activity and biological target in calycosin against atherosclerosis. We screened all preparative targets linked to calycosin and atherosclerosis from the available public databases. These results indicated total 409 putative targets in calycosin action, 71 of which were interacted with atherosclerosis. Further biological docking analysis suggested that calycosin displayed the powerful binding affinities with target proteins, including interleukin-6 (IL6) and mitogen-activated protein kinase 3 (MAPK3) MAPK3. Then enrichment findings revealed that calycosin action to treat atherosclerosis might be related to inhibition of inflammatory reaction and oxidative stress through modulating nucleolus transcription factor for improving lipid metabolism. In conclusion, the anti-atherosclerotic targets and molecular mechanisms in calycosin action were revealed systematically through preclinical evaluation. And calycosin may be a potential natural compound for the treatment of atherosclerosis.

Potential Role of Inflammasome NLRP3 and IL-1β Gene Expression in COVID-19 Patients: Impact of Ferritin and D –Dimer

Dysregulated inflammation and hypercoagulability underlie the development of severe illness in COVID-19. Biomarkers related to inflammasome activation, including interleukin (IL)-1β and NLRP3, and inflammatory lung cytokine as IL-8. As well as coagulation markers like D-dimer. The aim of this study was to identify associations between the dysregulated immune response biomarkers and the severity of the disease that will help in prognostic and potential therapeutic utility. Twenty five mild/moderate and 25 severe COVID-19 patients were included in this study as well as 25 healthy controls. Survival analysis was done after follow up for one month. Inflammasome (IL-1β, NLRP3), lung cytokine (IL-8), and vitamin D levels were analyzed by real time PCR and ELISA. The mRNA expression levels of IL-1β , NLRP3 and serum level of IL-8 were elevated in cases than controls. COVID-19 patients exhibited lower levels of vitamin D. The severe group showed significant higher levels of D dimer and ferritin. Correlation analyses indicated associations between IL-1β , NLRP3, IL-8, D-dimer and ferritin. ROC curve analyses demonstrated the potential of IL-1β , NLRP3 and IL-8 in distinguishing between mild/moderate and sever cases. Survival analyses indicated a link between high levels of IL-1β , NLRP3 and IL-8 with decreased survival.. The inflammasome appears pivotal in orchestrating detrimental hyperinflammation in severe COVID-19. IL-1β holds particular potential as a prognostic indicator of poor outcomes. In the future, the possible using of these biomarkers inhibitors may improve survival , decrease severity and improve management of the cases.

The association of inflammatory biomarkers and long-term clinical outcomes in older adults with non-ST elevation acute coronary syndrome

BackgroundThe prognostic significance of inflammatory markers on the long-term risk of major adverse cardiovascular and cerebrovascular events (MACCE) in older NSTEACS patients remains unclear. MethodsNSTEACS patients aged 75 and older were recruited to the multicentre cohort study Improve Cardiovascular Outcomes in High-Risk PatieNts with Acute Coronary Syndrome (ICON1). Inflammatory markers including interleukin-6 (IL-6), myeloperoxidase (MPO), high-sensitivity C-reactive protein (hsCRP), fibrinogen and tumor necrosis factor-alpha (TNF-α) were collected at baseline. Primary outcome was MACCE consisting of all-cause mortality, reinfarction, stroke/transient ischaemic attack, urgent revascularization, and significant bleeding at 5-year follow-up. ResultsThere were 230 patients with baseline IL-6 (median age 80.9 [interquartile range (IQR):78.2–83.9] years). High IL-6 was not associated with MACCE, but it was independently associated with all-cause mortality (adjusted hazard ratio [aHR]: 2.26 [95% Confidence Interval (CI):1.34–3.82]; P = 0.002). For patients with hsCRP (n = 260, median age 80.9 [IQR:77.9–84.1] years), higher levels were significantly associated with increased risk of MACCE (aHR:1.77 [95% CI:1.26–2.49], P = 0.001). In the cohort with MPO (230 patients, median age 80.9 [IQR:78.2–83.9] years), lower MPO was independently associated with the risk of MACCE (aHR: 0.67 [95%CI:0.46–0.96]; P = 0.029). There was no prognostic significance with fibrinogen and TNF-α. ConclusionAmong older NSTEACS patients, elevated IL-6 and hsCRP were associated with increased risk of all-cause mortality and MACCE, respectively. Low MPO levels were associated with higher MACCE. Further studies are required to determine how these biomarkers should influence treatment strategy in this understudied subset. Clinical Trial RegistrationNCT01933581

Increased TMEM166 Level in Patients with Postoperative Stroke after Carotid Endarterectomy

Postoperative stroke is a challenging and potentially devastating complication after elective carotid endarterectomy (CEA). We previously demonstrated that transmembrane protein 166 (TMEM166) levels were directly related to neuronal damage after cerebral ischemia–reperfusion injury in rats. In this subsequent clinical study, we aimed to evaluate the prognostic value of TMEM166 in patients suffering from post-CEA strokes. Thirty-five patients undergoing uncomplicated elective CEA and 8 patients who suffered ischemic strokes after CEA were recruited. We evaluated the protein level and expression of TMEM166 in patients diagnosed with postoperative strokes and compared it to those in patients who underwent uncomplicated elective CEA. Blood samples and carotid artery plaques were collected and analyzed. High expressions of TMEM166 were detected by immunofluorescence staining and Western Blot in carotid artery plaques of all patients who underwent CEA. Furthermore, circulating TMEM166 concentrations were statistically higher in post-CEA stroke patients than in patients allocated to the control group. Mean plasma concentrations of inflammatory markers, including interleukin 6 (IL-6) and C-reactive protein (CRP), were also elevated in patients with postoperative strokes. Therefore, based on these findings, we hypothesize that elevated TMEM166 levels, accompanied by a strong inflammatory response, serve as a useful biomarker for risk assessment of postoperative stroke following CEA.

Bimekizumab: A Review in Psoriatic Arthritis.

Although several biological disease-modifying antirheumatic drugs (bDMARDs), including interleukin (IL)-17A inhibitors, are approved for psoriatic arthritis, the treatment of this disease remains suboptimal. Bimekizumab (Bimzelx®), a dual IL-17A and IL-17F inhibitor, is approved in the EU, Great Britain and Japan for the treatment of psoriatic arthritis. In pivotal phase 3 clinical trials in patients who were bDMARD-naïve or previously had an inadequate response or intolerance to tumour necrosis factor (TNF) α inhibitors, bimekizumab improved the signs and symptoms of psoriatic arthritis across a range of joint, skin, radiographic and patient-reported outcomes compared with placebo, including the proportion of patients achieving a ≥ 50% response in the American College of Rheumatology criteria. Phase 2 clinical trial data have shown that responses are maintained up to 3 years. Bimekizumab was generally well tolerated in patients with psoriatic arthritis, with a safety profile consistent with that in other approved indications. The most common adverse events included nasopharyngitis, upper respiratory tract infection, oral candidiasis, headache and diarrhoea. In conclusion, bimekizumab extends the treatment options available to patients with psoriatic arthritis.

102 Circadian patterns of behavior, respiration, rectal temperature, saliva melatonin, cytokine concentrations, and milk immune cells are altered by cooling heat-stressed lactating sows

Abstract Lactating sows are particularly vulnerable to heat stress (HS) due to the increased metabolism from milk production. A greater understanding of HS response could assist in mitigating its detrimental effects on animal production. Two core circadian clock genes were pinpointed in a recent genome study as potential mediators of HS response, indicating the possible alteration of circadian clocks by HS exposure. This study aimed to assess how cooling of lactating sows under natural heat stress conditions in the summer influenced circadian patterns of respiration rate (RR), rectal temperature (RT), behaviors, salivary concentration of cortisol and melatonin, milk cell populations and relative abundance of multiple cytokines in saliva. Lactating sows of mixed parities were divided into two treatment groups: treated with electronic cooling pad (C; n=9) and heat-stressed control (H; n=9). Experiments were conducted during two 48 h periods of increased environmental temperatures from summer heatwaves. During the initial 48 h period, rectal temperature (RT) was monitored every 60 min, rectal temperature (RT) every 30 min, and behaviors of eating, standing, sitting, laying, sleeping, drinking, and nursing every 5 min. Morning milk samples were collected following the completion of the first phase and utilized to categorize and count somatic cells. The second trial was approximately 1 wk later, and during this period saliva samples were collected every 4 h over the 48-h period. Results were analyzed for significant effect of treatments and interaction using periodic regression while circadian patterns were further detected by incorporating a Fourier series model utilizing sine-cosine variables that denote a fit and/or shift in circadian pattern. The analysis revealed that cooling decreased RT and RR while also modifying circadian patterns (P &amp;lt; 0.05). Cooling had no impact on the percentage of time spent in any activity over the 48-h period (P &amp;gt; 0.05). Nevertheless, the daily patterns of eating, standing, and sitting were different between the treatments (P &amp;lt; 0.05). A shift in eating time to later in the day in H sows relative to C sows related to a second rise in RT during the dark phase of the light-dark cycle (P &amp;lt; 0.05). Saliva melatonin concentrations were increased in C sows and circadian pattern altered relative to H (P &amp;lt; 0.05), but there was no effect on salivary cortisol concentrations (P &amp;gt; 0.05). Cooling reduced milk lymphocytes (P &amp;lt; 0.05) and influenced diurnal pattern of saliva cytokines including interleukins (IL) IL-1 alpha, IL-1 beta, IL-10, and IL-15 and transforming growth factor-beta 1. In conclusion, the cooling of heat-stressed sows altered the circadian patterns of physiology, behavior and melatonin, suggesting the need for additional research to investigate whether circadian disruption contributes to reduced production efficiency observed in HS animals.

Interleukin 6 at menstruation promotes the proliferation and self-renewal of endometrial mesenchymal stromal/stem cells through the WNT/β-catenin signaling pathway.

At menstruation, the functional layer of the human endometrium sheds off due to the trigger of the release of inflammatory factors, including interleukin 6 (IL-6), as a result of a sharp decline in progesterone levels, leading to tissue breakdown and bleeding. The endometrial mesenchymal stem-like cells (CD140b+CD146+ eMSC) located in the basalis are responsible for the cyclical regeneration of the endometrium after menstruation. Endometrial cells from the menstruation phase have been proven to secrete a higher amount of IL-6 and further enhance the self-renewal and clonogenic activity of eMSC. However, the IL-6-responsive mechanism remains unknown. Thus, we hypothesized that IL-6 secreted from niche cells during menstruation regulates the proliferation and self-renewal of eMSC through the WNT/β-catenin signaling pathway. In this study, the content of IL-6 across the menstrual phases was first evaluated. Coexpression of stem cell markers (CD140b and CD146) with interleukin 6 receptor (IL-6R) was confirmed by immunofluorescent staining. In vitro functional assays were conducted to investigate the effect of IL-6 on the cell activities of eMSC, and the therapeutic role of these IL-6- and WNT5A-pretreated eMSC on the repair of injured endometrium was observed using an established mouse model. The endometrial cells secrete a high amount of IL-6 under hypoxic conditions, which mimic the physiological microenvironment in the menstruation phase. Also, the expression of IL-6 receptors was confirmed in our eMSC, indicating their capacity to respond to IL-6 in the microenvironment. Exogenous IL-6 can significantly enhance the self-renewal, proliferation, and migrating capacity of eMSC. Activation of the WNT/β-catenin signaling pathway was observed upon IL-6 treatment, while suppression of the WNT/β-catenin signaling impaired the stimulatory role of IL-6 on eMSC activities. IL-6- and WNT5A-pretreated eMSC showed better performance during the regeneration of the injured mouse endometrium. We demonstrate that the high level of IL-6 produced by endometrial cells at menstruation can induce the stem cells in the human endometrium to proliferate and migrate through the activation of the WNT/β-catenin pathway. Treatment of eMSC with IL-6 and WNT5A might enhance their therapeutic potential in the regeneration of injured endometrium.

Galantamine Reduces Blood Pressure and Renal Injury in Female Angiotensin II-induced Hypertensive Mice

Inflammation is a known culprit in the development and progression of hypertension. The autoimmune disease, systemic lupus erythematosus (SLE), is an important model of hypertension in the setting of chronic kidney inflammation. We have shown that administration of an acetylcholinesterase inhibitor, galantamine, attenuates the hypertension, kidney inflammation, and kidney injury in female SLE mice by activating the vagally-mediated cholinergic anti-inflammatory pathway. Although SLE hypertension represents a specific population of patients, we hypothesized that galantamine would have similar anti-inflammatory effects in the angiotensin II (AngII)-induced hypertensive mouse, which more commonly models essential hypertension. Female C57BL/6 mice were implanted with minipumps at 9 weeks of age for subcutaneous delivery of either AngII (1000 ng/kg/min) or saline (controls), and galantamine hydrobromide (4 mg/kg/day) or vehicle, for 21 days. At 12 weeks, carotid catheters were implanted and mean arterial pressure (MAP) was measured in conscious mice for two consecutive days. Mice were then euthanized, and kidneys collected. Markers of kidney inflammation and injury, including interleukin (IL)-6 and kidney injury molecule (KIM)-1, were measured by ELISA and normalized to total kidney protein. MAP (mmHg) was higher in AngII-treated mice compared to controls (174±4 vs. 133±3; n=4-5, p=0.0023). Galantamine lowered MAP in AngII mice (157±8; n=7, p=0.2567) without altering MAP in controls (133±4; n=5, p=0.9999). Renal IL-6 (pg/μg) was not different between AngII and control mice (0.004±0.0001 vs. 0.005±0.0006; p=0.6685). Although galantamine lowered IL-6 in both groups, it was only significant in controls (0.003±0.0002; p=0.0134) and not AngII mice (0.003±0.0003; p=0.4677). Renal cortical KIM-1 (pg/μg) trended higher in AngII mice compared to controls (2.53±0.50 vs 0.63±0.16; p=0.0741). Galantamine lowered KIM-1 in AngII mice (1.18±0.39, p=0.2064), but not controls (1.45 ± 0.59; p=0.6285). In summary, galantamine protected female mice from hypertension and renal injury in a model of AngII hypertension. This suggests that acetylcholinesterase inhibitor therapy may be effective in patients with hypertension. Studies funded by NIH R01HL153703 and K01HL139859 for KWM. 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.

Malvidin attenuates behavioral and inhibits the TNF-α/Caspase-3/Nrf-2 expression in rotenone-induced Parkinson's disease in rats: insights from molecular docking.

Malvidin is a natural, biologically active polyphenol found in several fruits. It exhibits several therapeutic benefits; however, limited studies are available on its effects on neurodegenerative clinical conditions, including Parkinson's disease. The study aimed to investigate the therapeutic properties of malvidin on rotenone-triggered Parkinson's disease in an animal model. To determine the effects of malvidin, rotenone (1.5 mg/kg) was injected subcutaneously into Wistar rats for 21 days, followed by a dose of malvidin (200 and 100 mg/kg). Behavioral tests were performed on the experimental animals before sacrifice. On the 22nd day of the experiment, biochemical tests were performed, including superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), and catalase (CAT). The activity of neurotransmitters and their metabolites, including acetylcholine (ACh), acetylcholinesterase (AChE), dopamine (DA), norepinephrine (NE), serotonin (5-HT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) along with neuroinflammatory markers including interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor- α (TNF-α), and nuclear factor erythroid 2-related factor 2 (Nrf-2) were estimated. Moreover, the level of the apoptotic marker, caspase-3, was also estimated. In addition, molecular docking was performed. The administration of rotenone resulted in oxidative stress, cholinergic imbalances, dopaminergic alternations, and increased expression of inflammatory compounds. The docking analysis revealed that malvidin displayed a favorable binding affinity for AChE, showcasing a binding energy of -9.329 Kcal/mol. The investigation concludes that malvidin exhibits neuroprotective effects due to its curative effects against inflammation and oxidative stress. These findings suggest that malvidin possesses therapeutic potential against rotenone-triggered behavioral, oxidative, and inflammatory abnormalities in rodents.

Mitochondrial antioxidant elamipretide improves learning and memory impairment induced by chronic sleep deprivation in mice.

The inflammation and synaptic dysfunction induced by mitochondrial dysfunction play essential roles in the learning and memory impairment associated with sleep dysfunction. Elamipretide (SS-31), a novel mitochondrion-targeted antioxidant, was proven to improve mitochondrial dysfunction, the inflammatory response, synaptic dysfunction, and cognitive impairment in models of cerebral ischemia, sepsis, and type 2 diabetes. However, the potential for SS-31 to improve the cognitive impairment induced by chronic sleep deprivation (CSD) and its underlying mechanisms is unknown. Adult c57BL/6J mice were subjected to CSD for 21 days using an activity wheel accompanied by daily intraperitoneal injection of SS-31 (5mg/kg). The novel object recognition and Morris water maze test were used to evaluate hippocampus-dependent cognitive function. Western blotting and reverse transcription-quantitative polymerase chain reaction assays were used to determine the effects of CSD and SS-31 on markers of mitochondria, inflammation response, and synaptic function. Enzyme-linked immunosorbent assays were used to examine the levels of proinflammatory cytokines. SS-31 could improve the cognitive impairment induced by CSD. In particular, SS-31 treatment restored the CSD-induced decrease in sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor γ coactivator alpha levels and the increase in levels nuclear factor kappa-B and inflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha. Furthermore, SS-31 significantly increased the levels of brain-derived neurotrophic factor, postsynaptic density protein-95, and synaptophysin in CSD mice. Taken together, these results suggest that SS-31 could improve CSD-induced mitochondrial biogenesis dysfunction, inflammatory response, synaptic dysfunction, and cognitive impairment by increasing SIRT1 expression levels.

Evaluation of antioxidant activity and fermentation properties of potential probiotic strain Lactiplantibacillus plantarum HY7720 in plant-based materials

People on vegan diets are at risk of being deficient in varied nutrients such as vitamin B12 and certain amino acids. In this study, we investigated vitamin B12-producing lactic acid bacteria (LAB) as well as the probiotic and antioxidant properties. Lactiplantibacillus plantarum HY7720 was screened from 22 strains of LAB that were isolated from different plant foods, and its growth ability and extracellular vitamin B12-producing capacity in vitamin B12-deficient medium were investigated. To determine whether HY7720 functions as a probiotic, survival rate in the simulated gastrointestinal tract and adhesion property to human intestinal epithelial cells of HY7720 were compared with positive control, Lacticaseibacillus rhamnosus GG (LGG). Moreover, the results showed that HY7720 recovered the gene expression levels of tight junction-associated proteins (TJPs), including TJP1, TJP2, occludin (OCLN), and claudin-1 (CLDN1) and inhibited the secretion levels of pro-inflammatory cytokines, including interleukin (IL)-6 and IL-8, in tumor necrosis factor (TNF)-α-stimulated Caco-2 cells. Furthermore, we verified that HY7720 exhibit the antioxidant potential, by showing its intracellular reactive oxygen species (ROS) scavenging ability in hydrogen peroxide (H2O2)-stimulated Caco-2 cells. The ability of HY7720 to ameliorate H2O2-induced cytotoxicity in Caco-2 cells was inhibited by mitogen-activated protein kinase (MAPK) inhibitors, indicating that its antioxidant responses are related to extracellular signal-regulated kinase (ERK) and c-JUN N-terminal kinase (JNK). This study also investigated the nutritional qualities of three plant-based materials (brown rice, white rice, and soy milk) fermented using HY7720. Collectively, HY7720 could be used as a promising probiotic strain for the prevention of nutritional deficiencies among people on vegetarian diets.

PM2.5 exposure upregulates pro-inflammatory protein expression in human microglial cells via oxidant stress and TLR4/NF-κB pathway

Exposure to ambient PM2.5 is associated with neurodegenerative disorders, in which microglia activation plays a critical role. Thus far, the underlying mechanisms for PM2.5-induced microglia activation have not been well elucidated. In this study, a human microglial cell line (HMC3) was used as the in vitro model to examine the inflammatory effect (hall marker of microglia activation) of PM2.5 and regulatory pathways. The expression of inflammatory mediators including interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2) as well as the brain derived neurotrophic factor (BDNF) were determined by ELISA and/or real-time PCR, respectively. Flow cytometry was used to measure the production of intracellular reactive oxygen species (ROS). Western blot was used to measure protein levels of Toll-like receptor 4 (TLR4), NF-κB inhibitor α (IκBα) and COX-2. It was shown that PM2.5 stimulation increased IL-6 and COX-2 expression but decreased BDNF expression in a dose-dependent manner. Further studies showed that PM2.5 triggered the formation of ROS and pre-treatment with the ROS scavenger acetylcysteine (NAC) significantly suppressed PM2.5-induced IL-6 and COX-2 expression. Moreover, the nuclear factor kappa B (NF-κB) inhibitor BAY11–7085 or the TLR4 neutralizing antibody markedly blocked PM2.5-induced IL-6 and COX-2 expression. However, NAC or BAY11–7085 exhibited minimal effect on PM2.5-induced BDNF down-regulation. In addition, pre-treatment with BAY11–7085 or TLR4 neutralizing antibody reduced ROS production induced by PM2.5, and NAC pre-treatment inhibited TLR4 expression and NF-κB activation induced by PM2.5. Collectively, PM2.5 treatment induced IL-6 and COX-2 but suppressed BDNF expression. PM2.5-induced IL-6 and COX-2 expression was mediated by interactive oxidative stress and TLR4/NF-κB pathway.

TSPO deficiency exacerbates acute lung injury via NLRP3 inflammasome-mediated pyroptosis.

Acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in many critically ill patients. Although inflammasome activation plays an important role in the induction of acute lung injury (ALI) and ARDS, the regulatory mechanism of this process is still unclear. When cells are stimulated by inflammation, the integrity and physiological function of mitochondria play a crucial part in pyroptosis. However, the underlying mechanisms and function of mitochondrial proteins in the process of pyroptosis are largely not yet known. Here, we identified the 18-kDa translocator protein (TSPO), a mitochondrial outer membrane protein, as an important mediator regulating nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation in macrophages during ALI. TSPO gene knockout (KO) and lipopolysaccharide (LPS)-induced ALI/ARDS mouse models were employed to investigate the biological role of TSPO in the pathogenesis of ARDS. Murine macrophages were used to further characterize the effect of TSPO on the NLRP3 inflammasome pathway. Activation of NLRP3 inflammasome was preformed through LPS+adenosine triphosphate (ATP) co-stimulation, followed by detection of mitochondrial membrane potential, reactive oxygen species (ROS) production, and cell death to evaluate the potential biological function of TSPO. Comparisons between two groups were performed with a two-sided unpaired t -test. TSPO- KO mice exhibited more severe pulmonary inflammation in response to LPS-induced ALI. TSPO deficiency resulted in enhanced activation of the NLRP3 inflammasome pathway, promoting more proinflammatory cytokine production of macrophages in LPS-injured lung tissue, including interleukin (IL)-1β, IL-18, and macrophage inflammatory protein (MIP)-2. Mitochondria in TSPO -KO macrophages tended to depolarize in response to cellular stress. The increased production of mitochondrial damage-associated molecular pattern led to enhanced mitochondrial membrane depolarization and pyroptosis in TSPO -KO cells. TSPO may be the key regulator of cellular pyroptosis, and it plays a vital protective role in ARDS occurrence and development.

Comprehensive plasma cytokine and chemokine profiling in prurigo nodularis reveals endotypes in Type 2 inflammation

Prurigo nodularis (PN) is a chronic inflammatory skin disease that is associated with variability in peripheral blood eosinophil levels and response to T-helper 2 targeted therapies (Th2). Our objective was to determine whether circulating immune profiles with respect to type 2 inflammation differ by race and peripheral blood eosinophil count. Plasma from 56 PN patients and 13 matched healthy controls was assayed for 54 inflammatory biomarkers. We compared biomarker levels between PN and HCs, among PN patients based on absolute eosinophil count, and across racial groups in PN. Eleven biomarkers were elevated in PN versus HCs including interleukin (IL)-12/IL-23p40, tumor necrosis factor-alpha (TNF-α), Thymic stromal lymphopoietin (TSLP), and macrophage-derived chemokine (MDC/CCL22). Additionally, PN patients with AEC > 0.3 K cells/μL had higher Th2 markers (eotaxin, eotaxin-3, TSLP, MCP-4/CCL13), and African American PN patients had lower eosinophils, eotaxin, and eotaxin-3 versus Caucasian and Asian PN patients (p < 0.05 for all). Dupilumab responders had higher AEC (p < 0.01), were more likely to be Caucasian (p = 0.02) or Asian (p = 0.05) compared to African Americans, and more often had a history of atopy (p = 0.08). This study suggests that blood AEC > 0.3 K and Asian and Caucasian races are associated with Th2 skewed circulating immune profiles and response to Th2 targeted therapies.