Significant Reduction In TNF-α Research Articles

CGF therapy: bridging androgenetic alopecia observations to psoriasis treatment via IL-17 pathway.

Concentrated Growth Factor (CGF), rich in CD34 + stem cells, is widely used in treatments for androgenetic alopecia and skin rejuvenation due to its immune-modulating properties. Psoriasis, a chronic inflammatory skin condition, presents significant treatment challenges, particularly for patients who cannot use biologics due to conditions such as cancer and lesions resistant to treatments. The potential of CGF in treating psoriasis is promising, given its broad immunoregulatory effects which confirmed in our previous androgenetic alopecia work. We evaluated the impact of CGF on IL-17 levels in two contexts: patients treated for androgenetic alopecia and a psoriasis mouse model. Twelve patients received three monthly injections of CGF, with serum IL-17 levels measured before and after treatment. In the psoriasis mouse model, groups were treated with CGF, and outcomes were assessed using the Psoriasis Area and Severity Index (PASI), skin barrier scores, histological analysis, and RNA sequencing. Additionally, in vitro experiments applied CD34 + cells from CGF to keratinocytes to measure levels of TNF-α, IFN-γ, IL-23, and IL-17. In patients with androgenetic alopecia, three monthly CGF injections resulted in significantly reduced serum IL-17 levels. In the psoriatic mouse model, CGF-treated groups exhibited lower PASI scores and improved skin barrier scores compared to controls. Histological analysis revealed enhanced skin characteristics, while RNA sequencing demonstrated downregulated IL-17 and upregulated CD34 expression, as well as improved expression of barrier-related genes. In vitro, the application of CD34 + cells from CGF to keratinocytes led to a significant reduction in TNF-α, IFN-γ, IL-23, and IL-17 levels, indicating strong anti-inflammatory effects. A clinical case of a psoriasis patient unresponsive to IL-23 therapy (Guselkumab) showed significant improvement following CGF treatment. These findings indicate that CGF could serve as an effective and versatile treatment for psoriasis, especially for patients who have already undergone biologic therapies but continue to experience resistant lesions.

Anti-Inflammatory and Antioxidant Potential of Green Synthesized Iron Zinc Oxide (Fe0.25-ZnO) Nanoparticles of the Elaeagnus angustifolia.

Research interest in examining Elaeagnus angustifolia's potential as a source of anti-inflammatory and antioxidant agents has grown as a result of the plant's endorsement as a rich source of bioactive chemicals with promising anti-inflammatory and antioxidant activity. In this study, zinc oxide (Fe0.25-ZnO) bimetallic nanoparticles (E.ang-Fe0.25-ZnO NPs) were synthesized using an aqueous extract of Elaeagnus angustifolia. Synthesized Fe0.25-ZnO nanoparticles were characterized by FTIR and XRD. The anti-inflammatory and antioxidant activities were investigated in LPS-stimulated RAW 264.7 macrophages using RT-PCR and ELISA techniques for antioxidant- and inflammation-related genes. The concentration of 39.6 μg/ml of E.ang-Fe0.25-ZnO NPs demonstrated a significant anti-inflammatory activity by suppressing the mRNA levels of TNF-α and IL-6 by 88.3 %±1.9 and 93.6 %±0.1, respectively, compared to LPS-stimulated cells. This was confirmed by the significant reduction of TNF-α and IL-6 secretion levels from 95.2 and 495.6 pg/ml in LPS-stimulated cells to 5.6 and 26.5 pg/ml in E.ang-Fe0.25-ZnO treated group. In addition, E.ang-Fe0.25-ZnO NPs nanoparticles treatment significantly enhanced the expression of antioxidant-related genes, SOD and CAT. Together, our results proved that phyto-mediated Fe0.25-ZnO nanoparticles using Elaeagnus angustifolia have great potential in biomedical applications such as anti-inflammatory and antioxidant.

Adjuvant antimicrobial photodynamic therapy improves periodontal health and reduces inflammatory cytokines in patients with type 1 diabetes mellitus.

Antimicrobial photodynamic therapy (aPDT) is an adjuvant treatment to scaling and root planing (SRP) which improves periodontal health. It may be beneficial to patients with systemic diseases, such as type 1 diabetes mellitus. This randomized clinical trial evaluated the adjunctive effect of aPDT on the periodontal treatment of patients with type 1 diabetes (T1D). 38 patients were included in the study and divided into four groups: DSRP - T1D patients treated with SRP; CSRP - normoglycemic patients treated with SRP; DPDT - T1D patients treated with SRP + aPDT (methylene blue and red laser); CPDT - normoglycemic patients treated with SRP + aPDT. , Periodontal clinical parameters and inflammatory cytokines in crevicular fluid were recorded at baseline and then after 1, 3 and 6 months. The clinical endpoint for treatment was evaluated after 6 months. Adjuvant aPDT treatment resulted in reduction of probing depth after 3 months (0.38 mm - p<0.05) on T1D patients and in control group after 6 months (0.66 mm - p<0.05). Reduction of clinical attachment levels was similar for both treatments in control patients (p>0.05). There was a significant reduction of TNF-α in crevicular fluid in both groups treated with aPDT (p<0.05). The T1D (65%) and normoglycemic (72%) groups achieved the clinical endpoint after both treatments (p>0.05). Adjuvant aPDT provided additional benefits in improving periodontal clinical parameters and reducing inflammatory cytokines in both T1D and normoglycemic patients. However, normoglycemic patients showed greater clinical improvements compared to T1D patients following adjuvant aPDT treatment.

Use of Zinc Nanoparticles and/or Prodigiosin to Mitigate Heat Stress in Rabbits

Abstract Heat stress (HS) is an environmental challenge affecting animals’ health, productivity and welfare. This work aimed to inspect the protective effect of zinc oxide nanoparticles (ZnNPs) and/or prodigiosin (PRG) against inflammation, immune dysfunction, oxidative stress and endoplasmic reticulum (ER) stress triggered by HS in growing rabbits. Growing weaned rabbits (one hundred males, 35 days of age) were randomly assigned into four groups. The first group was fed a basal diet without supplementation and the 2nd, 3rd, and 4th groups were fed diets containing zinc oxide nanoparticles (ZnNPs, 50 mg/kg diet), prodigiosin (PRG, 100 mg/kg diet) or their mixture (ZnPRG) under HS conditions for eight successive weeks. The dietary inclusion with ZnNPs and/or PRG significantly boosted FBW (final body weight), CBWG (cumulative body weight gain), and FCR (feed conversion ratio) and had no substantial impacts on the CFI (cumulative feed intake) as compared with those in HS one. All supplemented treatments significantly unveiled an increase in the values of RBCs, hemoglobin, and platelets and significant decreases in WBCs, basophils and monocytes with non-statistical effects on hematocrit, MCV, MCHC, neutrophils and eosinophils. Compared with the HS group, all supplemental groups showed a significant reduction in TNFα, IL4, IFN-γ, TLR-4 and amyloid A levels and DNA damage markers (OHdG) and significant increases in the levels of NO and lysosome activity. Rabbits in the ZnPRG group had significantly higher IgG and IgM levels compared to other groups. The highest value of CAT and GSH levels were found in rabbits that received the mixture of ZnNPs (50 mg) and prg (100 mg) in their diets under elevated temperatures. Additionally, both treatments, PRG and ZnNPS, significantly (P&lt;0.001) reduced the values of MDA and MYO, while all treated groups had significantly reduced PC contents compared with the HS group. Co-supplement with ZnPRG showed a considerable restoration in the higher immune expression of reticulum oxidative stress such as GRP78 and IRE1 in hepatic tissues induced by hs conditions. The mixture of ZnNPS and prg presented more robust effects in mitigating the adverse impacts of hs in rabbits compared with the individual treatments. Collectively, ZnNps and/or PRG alleviated oxidative stress and dna damage. In addition, it enhanced the antioxidant capacity and immune function, and downregulated ER stress such as GRP78 and IRE1 signaling in the hepatic tissues of stressed rabbits.

Myeloid Vamp3 deletion attenuates CFA-induced inflammation and pain in mice via ameliorating macrophage infiltration and inflammatory cytokine production.

Persistent inflammation and associated pain significantly impact individuals' quality of life, posing substantial healthcare challenges. Proinflammatory cytokines, released by activated macrophages, play crucial roles in the development of chronic inflammatory conditions such as rheumatoid arthritis. To identify and evaluate potential therapeutic interventions targeting this process for mitigating inflammation and pain, we created myeloid cell-specific knockout of Vamp3 (vesicle-associated membrane protein 3) mice (Vamp3 Δmyel) by crossing LysM-Cre mice with newly engineered Vamp3flox/flox mice. Bone marrow-derived macrophages and peritoneal resident macrophages from Vamp3 Δmyel mice exhibited a significant reduction in TNF-α and IL-6 release compared to control mice. Moreover, Vamp3 deficiency led to decreased paw edema and ankle joint swelling induced by intraplantar injection of complete Freund's adjuvant (CFA). Furthermore, Vamp3 depletion also mitigated CFA-induced mechanical allodynia and thermal hyperalgesia. Mechanistically, Vamp3 loss ameliorated the infiltration of macrophages in peripheral sites of the hind paw and resulted in reduced levels of TNF-α and IL-6 in the CFA-injected paw and serum. RT-qPCR analysis demonstrated downregulation of various inflammation-associated genes, including TNF-α, IL-6, IL-1β, CXCL11, TIMP-1, COX-2, CD68, and CD54 in the injected paw at the test day 14 following CFA administration. These findings highlight the novel role of Vamp3 in regulating inflammatory responses and suggest it as a potential therapeutic target for the development of novel Vamp-inactivating therapeutics, with potential applications in the management of inflammatory diseases.

Distinguishing the effects of systemic CSF1R inhibition by PLX3397 on microglia and peripheral immune cells

Microglia, the primary immune cells of the central nervous system (CNS), are derived from the yolk sac and populate the brain during development. Once microglia migrate to the CNS, they are self-renewing and require CSF1R signaling for their maintenance. Pexidartinib (PLX3397, PLX), a small molecule inhibitor of the CSF1R, has been shown to effectively deplete microglia since microglial maintenance is CSF1R-dependent. There have, however, been several conflicting reports that have shown the potential off-target effects of PLX on peripheral immune cells particularly those of lymphoid origin. Given this controversy in the use of the PLX family of drugs, it has become important to ascertain to what extent PLX affects the peripheral immune profile in lymphoid (spleen, and bone marrow) and non-lymphoid (kidney, lungs, and heart) organs. PLX3397 chow treatment at 660 mg/kg for 7 days significantly reduced CD45+ macrophages, CX3CR1-GFP cells, CD11b+CD45intermediate cells, and P2RY12 expression in the brain. However, there were minimal effects on peripheral immune cells from both lymphoid and non-lymphoid organs except in the heart where there was a significant decrease in CD3+ cells, inflammatory and patrolling monocytes, and CD11b+Ly6G+ neutrophils. We then stimulated the immune system with 1 mg/kg of LPS which resulted in a significant reduction in the number of innate immune cells. In this context, PLX did not alter the cytokine profile in the serum and the brain of naïve mice but did so in the LPS-stimulated group resulting in a significant reduction in TNFα, IL-1α, IFN-γ and IL-1β. Furthermore, PLX did not alter locomotor activity in the open field test suggesting that microglia do not contribute to LPS-induced sickness behavior. Our results provide an assessment of immune cell populations with PLX3397 treatment on brain, lymphoid and non-lymphoid organs without and during LPS treatment that can serve as a resource for understanding consequences of such approaches.

The Effect of G. applanatum Crude Polysaccharide Extract on Proinflammatory Cytokines and Proapoptotic Caspases in HeLa Cell Line: An In Vitro Study.

Polysaccharide extracts exhibit promise as potential anticancer agents. Among the fungi rich in polysaccharide content, G. applanatum stands out; however, its anticancer activity necessitates further investigation. This study aims to explore the impact of G. applanatum crude polysaccharide (GACP) extract by assessing its effects on cell viability, levels of proinflammatory cytokines such as TNF-α, IFN-γ, IL-2, and IL-12, and levels of proapoptotic markers including caspase-3 and caspase-9, as well as the percentages of necrosis and apoptosis in the HeLa cell line. Employing the HeLa cell line as a research model, four groups were studied: KN (media and DMSO), K+ (doxorubicin 10 μg/mL), P1 (G. applanatum extract 200 μg/mL), and P2 (G. applanatum extract 400 μg/mL). The G. applanatum extract was obtained via boiling distilled water. Anticancer activity was evaluated through the MTT test (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide) conducted over three treatment durations (24, 48, and 72 hours). Cytokine levels and caspase-3 and caspase-9 levels were assessed using the ELISA test. Cell apoptosis was determined using the Annexin V-PI biomarker and analyzed through flow cytometry. The MTT test exhibited optimal results at the 48-hour treatment mark. Cytokine level analysis revealed significant reductions in TNF-α, IFN-γ, IL-2, and IL-12 levels (p < 0.005). Concurrently, caspase-3 and caspase-9 levels exhibited substantial increases (p < 0.005). Flow cytometry highlighted the highest percentage of apoptosis in HeLa cells. In conclusion, G. applanatum's polysaccharide extract demonstrates potential as an anticancer and therapeutic agent for cancer treatment.

The immunomodulatory effects of lactoferrin and its derived peptides on NF-κB signaling pathway: A systematic review and meta-analysis.

Lactoferrin is a versatile protein with important modulatory functions in inflammation and immune response. This glycoprotein can bind and sequester iron and LPS, thereby intervening in certain signaling pathways and biological processes. In the present meta-analysis, we aimed to pool experimental data regarding the immunomodulatory effects of lactoferrin and its derived peptides on the NF-κB signaling pathway. We searched PubMed, Google Scholar, and Web of Science databases and obtained all related articles published before April 2022. Finally, 25 eligible studies were selected, and their reports were analyzed. We used Review Manager Version 5.2 to compute the standardized mean difference (SMD) and its 95% confidence interval. In addition, the source of heterogeneity was explored using meta-regression and sensitivity analysis. The symmetry of the funnel plot and Egger's test were also used to evaluate publication bias utilizing Comprehensive Meta-Analysis Version 2. Comparing the group of cells and animals exposed to lipopolysaccharide alone with the group that received pretreatment with lactoferrin and its derivatives, we observed significant reductions in TNF-α, IL-1 beta, and IL-6 levels by 8.73 pg/mL, 2.21 pg/mL, and 3.24 pg/mL, respectively, in the second group. Additionally, IKK-β, p-IκB, and NF-κB (p65) levels were significantly lower by 7.37-fold, 15.02-fold, and 3.88-fold, respectively, in various cells and tissues. Based on the results of this meta-analysis, lactoferrin and its derived peptides can be considered potent prophylactic and therapeutic candidates against inflammation-associated diseases by targeting the NF-kB pathway.

Novel promising benzoxazole/benzothiazole-derived immunomodulatory agents: Design, synthesis, anticancer evaluation, and in silico ADMET analysis.

Eleven novel benzoxazole/benzothiazole-based thalidomide analogs were designed and synthesized to obtain new effective antitumor immunomodulatory agents. The synthesized compounds were evaluated for their cytotoxic activities against HepG-2, HCT-116, PC3, and MCF-7 cells. Generally, the open analogs with semicarbazide and thiosemicarbazide moieties (10, 13a-c, 14, and 17a,b) exhibited higher cytotoxic activities than derivatives with closed glutarimide moiety (8a-d). In particular, compound 13a (IC50 = 6.14, 5.79, 10.26, and 4.71 µM against HepG-2, HCT-116, PC3, and MCF-7, respectively) and 14 (IC50 = 7.93, 8.23, 12.37, and 5.43 µM, respectively) exhibited the highest anticancer activities against the four tested cell lines. The most active compounds 13a and 14 were further evaluated for their in vitro immunomodulatory activities on tumor necrosis factor-alpha (TNF-α), caspase-8 (CASP8), vascular endothelial growth factor (VEGF), and nuclear factor kappa-B p65 (NF-κB p65) in HCT-116 cells. Compounds 13a and 14 showed a remarkable and significant reduction in TNF-α. Furthermore, they showed significant elevation in CASP8 levels. Also, they significantly inhibited VEGF. In addition, compound 13a showed significant decreases in the level of NF-κB p65 while compound 14 demonstrated an insignificant decrease with respect to thalidomide. Moreover, our derivatives exhibited good in silico absorption, distribution, metabolism, elimination, toxicity (ADMET) profiles.

Design, synthesis, anticancer evaluation, in silico docking and ADMET analysis of novel indole-based thalidomide analogs as promising immunomodulatory agents

In the present work, novel 16 indole-based thalidomide analogs were designed and synthesized to obtain new effective antitumor immunomodulatory agents. The synthesized compounds were evaluated for their cytotoxic activities against HepG-2, HCT-116, PC3 and MCF-7 cell lines. Generally, the opened analogs of glutarimide ring exhibited higher activities than the closed ones. Compounds 21a–b and 11d,g showed strong potencies against all tested cell lines with IC50 values ranging from 8.27 to 25.20 µM comparable to that of thalidomide (IC50 values ranging from 32.12 to 76.91 µM). The most active compounds were further evaluated for their in vitro immunomodulatory activities via estimation of human tumor necrosis factor alpha (TNF-α), human caspase-8 (CASP8), human vascular endothelial growth factor (VEGF), and nuclear factor kappa-B P65 (NF-κB P65) in HCT-116 cells. Thalidomide was used as a positive control. Compounds 11g, 21a and 21b showed remarkable significant reduction in TNF-α. Furthermore, compounds 11g, 21a and 21b showed significant elevation in CASP8 levels. Compounds 11g and 21a significantly inhibited VEGF. In addition, derivatives 11d, 11g and 21a showed significant decrease in level of NF-κB p65. Moreover, our derivatives exhibited good in silico docking and ADMET profile. Communicated by Ramaswamy H. Sarma

Immunohistochemical neuroinflammatory markers in the hippocampus of PTZ-kindled rats under conditions of rapamycin and axitinib treatment

The aim of the study is to determine the level of HIF-1α, TNF-α, and NF-kB in the hippocampus of kindled rats treated with rapamycin and axitinib.&#x0D; Materials and methods. Kindling was produced in 29 rats by administration of three-week pentylenetetrazole (PTZ, 35.0 mg/kg, i.p.). Treatment with rapamycin (0.5 mg/kg, i.p.) and axitinib (2.5 mg/kg, i.p.) was performed for ten days in fully kindled rats. The avidin-biotin-peroxidase method was used for hippocampal slice staining. For negative control, staining was performed using only secondary antibodies.&#x0D; Results. The HIF-1α expression increased in kindled rats raised by 1.77 times compared to the control (p&lt;0.001). Axitinib treatment resulted in of HIF-1α level of 16.7 % (p&lt;0.05) compared with kindled animals, while combined treatment with rapamycin and axitinib reduced HIF-1α by 33.8 % (p&lt;0.01). In kindled rats, TNF-α expression was 3.74 times greater than in control (p&lt;0.001). Rapamycin treatment reduced TNF-α by 31.0 % (p&lt;0.01). Axitinib treatment caused a reduction of TNF-α by 21.1 % (p&lt;0.05). Combined treatment with rapamycin and axitinib reduced TNF-α by 48.0 % (p&lt;0.001) but still exceeded the TNF-α in control by 1.95 times (p&lt;0.01). NF-kB level in kindled rats exceeded the control by three times (p&lt;0.001). Rapamycin caused a reduction of 19.3 % (p&gt;0.05), while axitinib – by 26.5 % (p&lt;0.05) compared with kindled rats. Combined treatment with rapamycin and axitinib resulted in NF-kB reduction by 56.7 % compared with kindled rats (p&lt;0.001). &#x0D; Conclusions. PTZ-kindling resulted in an increase in the immunoreactivity of HIF-1α, TNF-α, and NF-kB in the hippocampus. Combined treatment with rapamycin and axitinib engendered prevention of generalized seizures and normalized the level of HIF-1α and NF-kB with a significant reduction of TNF-α. Effects of treatment favours of synergy action of rapamycin and axitinib

RETRACTED ARTICLE: Polyphenols from Conyza dioscoridis (L.) ameliorate Alzheimer’s disease- like alterations through multi-targeting activities in two animal models

BackgroundRecent investigations suggested that anticancer agents may inhibit the progression of Alzheimer's disease (AD) pathology. Conyza dioscoridis (L.) was demonstrated to have anticancer, antioxidant, anti-inflammatory and antidiabetic effects. This study was carried out to investigate the efficacy of polyphenols from Conyza dioscoridis (L.) extract (PCDE) on AD.MethodsImpacts of 3 doses of PCDE and donepezil, a reference drug, on the features of Alzheimer's disease in two animal models were investigated.ResultsPCDE ameliorated the memory and learning impairment shown in rats following a single dose of scopolamine (scopolamine model) or 17 weeks of high-fat/high-fructose(HF/Hfr) diet coupled with a single dose of streptozotocin, (25 mg/kg) (T2D model). They reduced significantly the high hippocampal cholinesterase activity in the two models of rats. Administration of PCDE for 8 weeks in the T2D model showed a significant reduction in hippocampal GSK-3β, caspase-3 activity and increase in the inhibited glutamate receptor expression (AMPA GluR1 subunit and NMDA receptor subunits NR1, NR2A, NR2B). A significant reduction of HOMA-insulin resistance and serum hypercholesterolemia was observed. The Tau hyperphosphorylation and Aβ 1–42 generation in the hippocampal of T2D rats were significantly decreased by PCDE. Modulation of the oxidative stress markers, (rise in GH and SOD; decrease in MDA levels) and a significant reduction of TNF-α and IL-1β in the hippocampus of T2D rats treated by PCDE extract were important findings in this study. The highest dose tested was 4% of the highest safe dose.ConclusionOur study suggests that PCDE is multi-targeting agent with multiple beneficial activities in combating features of AD. This study may provide a novel therapeutic strategy for AD treatment that warrants clinical studies.

Recellularized bovine pericardium with autologous mesenchymal stem cells reduces immune activation.

Current bioprosthetic heart valve replacement options are limited by structural valvular deterioration (SVD) due to an immune response to the xenogenic scaffold. Autologous mesenchymal stem cell (MSC) recellularization is a method of concealing xenogenic scaffolds, preventing recipient immune recognition of xenogenic tissue heart valves, and potentially leading to reduction in SVD incidence. The purpose of this study is to examine the effects of autologous MSC recellularized tissue on the immune response of human whole blood to bovine pericardium (BP). We hypothesized that autologous MSC recellularization of BP will result in reduced pro-inflammatory cytokine production equivalent to autologous human pericardium. Bone marrow, human pericardium, and whole blood were collected from adult patients undergoing elective cardiac surgery. Decellularized BP underwent recellularization with autologous MSCs, followed by co-incubation with autologous whole blood. Immunohistochemical, microscopic, and quantitative immune analysis approaches were used. We demonstrated that native BP, exposed to human whole blood, results in significant TNF-α and IL1β production. When decellularized BP is recellularized with autologous MSCs and exposed to whole blood, there is a significant reduction in TNF-α and IL1β production. Importantly, recellularized BP exposed to whole blood had similar production of TNF-α and IL1β when compared to autologous human pericardium exposed to human whole blood. Our results suggest that preventing initial immune activation with autologous MSC recellularization may be an effective approach to decrease the recipient immune response, preventing recipient immune recognition of xenogeneic tissue engineered heart valves, and potentially leading to reduction in SVD incidence.

Citronellol exerts lung protective and anti‐inflammatory effects through hampering NF‐κB in lipopolysaccharide‐induced acute lung injury in mice

BackgroundAcute lung injury (ALI) is one of the most serious conditions characterized by an exacerbation of inflammatory response in the lungs that can result from lung infection. Citronellol, a natural monoterpenoid found in citronella oil and other natural sources. In this study, the lung protective and anti‐inflammatory effects of citronellol were investigated in ALI induced by Lipopolysaccharide (LPS) in mice.Methodadult mice were allocated into groups, control mice received normal saline. Mice in the induction group received LPS 10mg/kg/day intraperitoneally and euthanized 2 hours later. Mice in the treatment groups received either 50mg or 100mg/kg/day of oral citronellol for 5 consecutive days prior to LPS injection.ResultsPretreatment with citronellol (50mg/kg/day) attenuated lung inflammatory events as observed from the significant reduction of TNF‐α (6.02±1.039 vs 29.20±4.77) and COX2 (4.12±0.23 vs 10.58±0.77) mRNA expressions in lung tissue compared to non‐treated mice. Interestingly, increasing the dose of citronellol to 100mg/kg/day also resulted in a significant reduction in both TNF‐α (3.30±0.745 vs 29.20±4.77) and COX2 (4.62±0.58 vs 10.58±0.77) mRNA expression compared to non‐treated mice.Looking for the upstream events revealed that NF‐κB gene expression was significantly hampered by citronellol 50mg/kg/day (5.11 ± 1.096 vs 11.88±1.57) and 100mg/kg/day (3.22± 0.253 vs 11.88±1.57) compared to non‐treated mice. Analysis of the data revealed that the effect of citronellol were dose dependent in terms of TNF‐α and NF‐κB gene expression.ConclusionThis study clearly revealed that citronellol exerted anti‐inflammatory and lung‐protective effects in LPS‐induced acute lung injury. The observed effects were dose‐independent and resulted through hampering of NF‐κB pathway.

Liraglutide Attenuates Hepatic Ischemia-Reperfusion Injury by Modulating Macrophage Polarization.

Ischemia-reperfusion injury (IRI) is a common complication associated with liver surgery, and macrophages play an important role in hepatic IRI. Liraglutide, a glucagon-like peptide-1 (GLP-1) analog primarily used to treat type 2 diabetes and obesity, regulates intracellular calcium homeostasis and protects the cardiomyocytes from injury; however, its role in hepatic IRI is not yet fully understood. This study aimed to investigate whether liraglutide can protect the liver from IRI and determine the possible underlying mechanisms. Our results showed that liraglutide pretreatment significantly alleviated the liver damage caused by ischemia-reperfusion (I/R), as evidenced by H&E staining, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, and TUNEL staining. Furthermore, the levels of inflammatory cytokines elicited by I/R were distinctly suppressed by liraglutide pretreatment, accompanied by significant reduction in TNF-α, IL-1β, and IL-6 levels. Furthermore, pretreatment with liraglutide markedly inhibited macrophage type I (M1) polarization during hepatic IRI, as revealed by the significant reduction in CD68+ levels in Kupffer cells (KCs) detected via flow cytometry. However, the protective effects of liraglutide on hepatic IRI were partly diminished in GLP-1 receptor-knockout (GLP-1R-/-) mice. Furthermore, in an in vitro study, we assessed the role of liraglutide in macrophage polarization by examining the expression profiles of M1 in bone marrow-derived macrophages (BMDMs) from GLP-1R-/- and C57BL/6J mice. Consistent with the results of the in vivo study, liraglutide treatment attenuated the LPS-induced M1 polarization and reduced the expression of M1 markers. However, the inhibitory effect of liraglutide on LPS-induced M1 polarization was largely abolished in BMDMs from GLP-1R-/- mice. Collectively, our study indicates that liraglutide can ameliorate hepatic IRI by inhibiting macrophage polarization towards an inflammatory phenotype via GLP-1R. Its protective effect against liver IRI suggests that liraglutide may serve as a potential drug for the clinical treatment of liver IRI.

Basil (Ocimum basilicum) Leaves Essential Oil Ameliorates GluR1 Receptor Expression, TNF-α Level, and Pain-like Behaviors in Post-operative Pain Setting

Abstract Background: Unrelieved post-operative pain is an emerging healthcare concern with ever increasing global volume of surgical procedures. GluR1 subunit coupled with tumor necrosis factor (TNF)-α expression plays a major role in the development of post-operative pain mediated by α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor. There was no existing evidence on the analgesic potential of basil essential oil (BEO) in post-operative settings, despite its well-established antinociceptive and anti-inflammatory activities. Materials and Methods: BEO was subjected to gas chromatography–mass spectrometry (GC–MS) analysis to identify the active ingredients. The antinociceptive and anti-inflammatory activities of orally administrated basil (Ocimum basilicum) essential oil were tested in a rat model of post-operative pain using hindpaw surgical incision as noxious stimuli. TNF-α and GluR1 subunit expressions were measured using enzyme-linked immunosorbent assay and immunohistochemistry methods. Spontaneous pain and mechanical hyperalgesia were measured using mouse grimace scale and Von Frey monofilament test, respectively. All outcomes were evaluated in acute post-operative pain timeframe. Results: Chemical analysis identified 14 terpenoids predominated with caryophyllene and citral. BEO administration caused a significant reduction of TNF-α (67.23 ± 2.46 vs. 70.45 ± 4.89; P = 0.019) and GluR1 (3.03 ± 0.56 vs. 3.90 ± 1.12; P = 0.005) levels at 24 h after surgical incision when compared with the control group. Significant spontaneous pain, pain threshold, and pain-like behaviors frequency reduction at 1-, 4-, and 24-h post-surgical incision were also noted. Conclusion: Effective antinociceptive activity of BEO through modulation of GluR1 and TNF-α levels was further confirmed in the behavioral outcome. Advancement into clinical translation necessitates BEO pharmacological profiling, especially given the diversity of chemotypes.

Effect of Arrabideae chica (crajiru) extract in a model of induced experimental colitis in rats

Objective: This study aimed to investigate the effect of A. chica extract on the evolution of experimental rectocolitis in rats, and the expression of the pro-inflammatory cytokines TNF-a, IL-1β and IL-6 in colonic tissue. Methods: Wistar rats weighing 275±23g were distributed into 4 groups of 6 animals each. Rectocolitis was induced in rats by rectal administration of trinitrobenzene sulfonic acid (TNBS). Seventy-two hours after TNBS injection, animals were treated daily for 6 days. Groups: 1. Normal control group without induction of rectocolitis. Received 0.9% saline injection v.o. by gavage during treatment. 2. TNBS rectocolitis group, treated with normal saline (SN) by gavage (TNBS+SN); 3. TNBS rectocolitis group treated with A. chica extract (ACE), receiving a daily dose of 300 mg of A. chica extract by gavage (TNBS+ACE);4. TNBS rectocolitis group treated with mesalazine, receiving a daily dose of 100 mg/kg of mesalazine orally (TNBS+MEZ). Macroscopic examination of the colon and dosing of TNF-α, IL-1β and IL-6 in colon tissue were performed. Results: There was a reduction in weight in animals treated only with TNBS+NS. No difference in weight was observed comparing the animals treated with ACE and MEZ. In the control group no mucosal ulcers or edema of the colon wall were observed. Several mucosal ulcers, edema and hyperemia occurred in the colon of rats in the TNBS+SN group. In two of the animals in this group there was colon perforation, tamponated by omentum. A reduction of mucosal ulcers number in the TNBS+ACE (crajiru) group was seen, compared to the TNBS+SN and TNBS+MEZ group. There was a significant reduction of TNF-α, IL-1β and IL-6 in the colon tissue of animals treated with crajiru extract, TCBS+ACE group, when compared to the control group (p&lt;0.001), TNBS+SN group, and TNBS+MEZ groups (p&lt;0.001). Conclusion: This is the first study to show that A. chica extract positively influences the treatment of TNBS/induced rectocolitis through its antiinflamatory activity. More comprehensive studies are needed to understand the underlying mechanisms.

SARS-CoV-2 Spike Glycoprotein S1 Induces Neuroinflammation in BV-2 Microglia

In addition to respiratory complications produced by SARS‐CoV‐2, accumulating evidence suggests that some neurological symptoms are associated with the disease caused by this coronavirus. In this study, we investigated the effects of the SARS‐CoV‐2 spike protein S1 stimulation on neuroinflammation in BV-2 microglia. Analyses of culture supernatants revealed an increase in the production of TNF-α, IL-6, IL-1β and iNOS/NO. S1 also increased protein levels of phospho-p65 and phospho-IκBα, as well as enhanced DNA binding and transcriptional activity of NF-κB. These effects of the protein were blocked in the presence of BAY11-7082 (1 µM). Exposure of S1 to BV-2 microglia also increased the protein levels of NLRP3 inflammasome and enhanced caspase-1 activity. Increased protein levels of p38 MAPK was observed in BV-2 microglia stimulated with the spike protein S1 (100 ng/ml), an action that was reduced in the presence of SKF 86,002 (1 µM). Results of immunofluorescence microscopy showed an increase in TLR4 protein expression in S1-stimulated BV-2 microglia. Furthermore, pharmacological inhibition with TAK 242 (1 µM) and transfection with TLR4 small interfering RNA resulted in significant reduction in TNF-α and IL-6 production in S1-stimulated BV-2 microglia. These results have provided the first evidence demonstrating S1-induced neuroinflammation in BV-2 microglia. We propose that induction of neuroinflammation by this protein in the microglia is mediated through activation of NF-κB and p38 MAPK, possibly as a result of TLR4 activation. These results contribute to our understanding of some of the mechanisms involved in CNS pathologies of SARS-CoV-2.

The Effect of Probiotics in Stroke Treatment.

Objective We conducted a systematic review and meta-analysis to evaluate the curative effect of probiotics combined with enteral nutrition (EN) in patients with stroke. Methods We retrieved randomized controlled trials and case-controlled trials on the use of probiotics for stroke treatment from PubMed, Web of Science, CNKI, Wanfang, and Weipu databases. Retrieval times were from the databases' inception to November 6, 2020. Two researchers conducted a strict evaluation of the literature quality and extracted the data, which were then entered into RevMan 5.3 for meta-analysis. Results Twenty-three articles were included, including 1,816 patients. The meta-analysis revealed that probiotics combined with EN did not reduce NIHSS scores of patients with stroke (P > 0.05). However, it did shorten hospital stays and bedrest periods (P < 0.05). Probiotics combined with EN also improved patients' nutritional status and increased hemoglobin, albumin, serum total protein, and physical and chemical properties of prealbumin (P < 0.05). In terms of relieving inflammation, we found that probiotics combined with EN reduced neither high-sensitivity C-reactive protein nor procalcitonin (P > 0.05). However, it did cause a significant reduction in TNF-α, IL-6, and IL-10. Probiotics combined with EN significantly reduced esophageal reflux, bloating, constipation, diarrhea, gastric retention, and gastrointestinal bleeding. It relieved intestinal stress and reduced the occurrence of adverse reactions such as esophageal reflux, bloating, constipation, diarrhea, gastric retention, and gastrointestinal bleeding (P < 0.05). In terms of reducing stroke complications, probiotics combined with EN reduced the incidence of lung, gastrointestinal, and urinary tract infections (P < 0.05). It also reduced fatality rates and intestinal flora imbalance rates (P < 0.05). Conclusion The probiotics combined with EN group's therapeutic effects were superior to those of the EN alone. Thus, probiotics combined with EN is worthy of both clinical application and promotion in stroke treatment.

Serum biomarkers for chronic pancreatitis pain patterns

ObjectivesChronic pancreatitis (CP) is associated with debilitating refractory pain. Distinct subtypes of CP pain have been previously characterized based on severity (none, mild-moderate, severe) and temporal (none, intermittent, constant) nature of pain, but no mechanism-based tools are available to guide pain management. This exploratory study was designed to determine if potential pain biomarkers could be detected in patient serum and whether they associate with specific pain patterns. MethodsCytokines, chemokines, and peptides associated with nociception and pain were measured in legacy serum samples from CP patients (N = 99) enrolled in the North American Pancreatitis Studies. The unsupervised hierarchical cluster analysis was applied to cluster CP patients based on their biomarker profile. Classification and regression tree was used to assess whether these biomarkers can predict pain outcomes. ResultsThe hierarchical cluster analysis revealed a subset of patients with predominantly constant, mild-moderate pain exhibited elevated interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), and monocyte chemoattractant protein-1 (MCP1) whereas patients with higher interleukin-4 (IL-4), interleukin-8 (IL-8) and calcitonin gene related peptide (CGRP) were more likely to have severe pain. Interestingly, analyses of each individual biomarker revealed that patients with constant pain had reduced circulating TNFα and fractalkine. Patients with severe pain exhibited a significant reduction in TNFα as well as trends towards lower levels of IL-6 and substance P. DiscussionThe observations from this study indicate that unique pain experiences within the chronic pancreatitis population can be associated with distinct biochemical signatures. These data indicate that further hypothesis-driven analyses combining biochemical measurements and detailed pain phenotyping could be used to develop precision approaches for pain management in patients with chronic pancreatitis.