Tissue Necrosis Factor Research Articles

Evolving role of immunology in chronic pain medicine: tissue necrosis factor and interleukin modulatory treatments

Our immune system acts to protect us in times of stress and traumatic injury. As part of the immune response, the body produces various cytokines, which mediate or modulate immune functions. Such cytokines include tumor necrosis factor (TNF) and interleukin 6 (IL-6) and IL-17. These cytokines can also act on the nervous system to influence pain perception. TNF-α triggers an inflammatory response and two forms of programmed cell death, apoptosis and necroptosis, depending on the pathological state. For individuals with chronic conditions relating to immune deficiency, the actions of these cytokines can present as chronic pain states, significantly altering quality of life. One attractive potential solution for treating this immune linked pain is by altering signaling pathways of pain-enhancing cytokines. Infliximab and etanercept are TNF inhibitors that are currently on the market for use in the treatment of chronic pain. Secukinumab and tocilizumab serve as IL inhibitors, utilized for a similar purpose. These novel immunotherapies have shown efficacy in numerous clinical studies with acceptable side effect profiles. In this review, we summarize the pharmacological profiles of these drugs and discuss their usage in treating chronic pain.

TO EVALUATE THE INFLAMMATORY MARKERS IN TYPE 2 DIABETES MELLITUS AND COMPARED IT WITH NORMAL HEALTHY CONTROLS

Objective :To evaluate the serum levels of Interleukin -6, Tissue Necrosis factor – α, C- reactive Protein ( IL-6, TNF- α , CRP) in type 2 diabetes mellitus in North Population Method: A total of 200 participants were selected in this study among them 100 were recruited as Cases who were suffering from T2DM and 100 were healthy controls. Biochemical parameters were analyzed by fully autoanalyser. Serum levels of inflammatory cytokines, TNF-α ,CRP and IL-6 were estimated by ELISA . Data was analyzed using statistical ‘software SPSS 15. TheP<0.05 were considered as statistically significant. Result: in our study we observed that serum levels of candidate cytokines, TNF-α, IL-6 and CRP were highly significant (p<0.001) in T2DM as compared to healthy control. Fasting blood sugar, HbA1c and lipid profile parameters were recorded highly significant (p<0.001) in T2DM as compared to normal healthy controls. Conclusion: Inflammatory cytokines play a significant role in the pathogenesis of T2DM. Hence, these cytokines can be used as early prediction biomarkers which may be helpful in the reduction of mortality rate of T2DM.

Neuroprotective effect of Dark Chocolate on ketamine-induced animal model of psychosis through the reversal of behavioral, biochemical and histopathological changes

The present study was designed to evaluate the antipsychotic-like activity of dark chocolate against Ketamine-induced psychosis in animals and to explore the possible underlying mechanisms for this activity. Dark chocolate (200, 400 mg/kg, along with diet), haloperidol (1mg/kg, i.p.), and olanzapine (5mg/kg, i.p) were administered daily to different groups of mice and rats; after 30 min Ketamine was injected for 21 successive days. The antipsychotic- like activity was assessed using an actophotometer, stereotypic behaviors, forced swim test (FST), and passive avoidance test. Dark Chocolate (DC) and olanzapine remarkably decreased the immobility period of Ketamine-treated mice in FST, indicating the beneficial effect of DC against depressive or negative symptoms of psychosis. There was no significant effect on the locomotor activity of the mice with the administration of DC, while it showed a reducing impact against stereotypic behaviors. Furthermore, DC significantly reduced the time taken by the rats to climb the pole, showing the effect of DC on cognition. In addition, acetylcholinesterase (AChE) activity, malondialdehyde (MDA), and tissue necrosis factor (TNF-α) levels were markedly decreased and increased GABA and enhanced reduced glutathione (GSH) levels with the treatment of DC. Furthermore, DC was also effective in reducing the ketamine induced hyperchromatic nuclei, perinuclear vacuolization, and dilated vascular channels in the cortex part of the brain. Behavioral, biochemical, and histopathological studies suggest the protective effect of DC against Ketamine induced psychosis.

Anti-psoriatic evaluation of aloe emodin-loaded topical hydrogel in an imiquimod-induced human plaque-type psoriasis in BALB/c mice

Aloe emodin, an anthraquinone derivative, mainly obtained from Aloe vera, possesses an extensive spectrum of pharmacological properties, including anti-proliferative, anticancer, wound healing, analgesic, anti-inflammatory, antibacterial, and antiviral properties. The objective of the present study was to prepare aloe emodin-loaded topical hydrogel formulations for managing plaque-type psoriasis. Different proportions of carbopol 940, chitosan, and hydroxyl propyl methyl cellulose K15M (HPMC K15M) were used as gelling agents. The prepared hydrogels were characterized for pH, viscosity, rheological behavior, spreadability, extrudability, swelling index, drug content, and accelerated stability. Based on physicochemical and in vitro permeation studies, PHGL1 containing aloe emodin (1%) and carbopol 940 (1%) was selected. The acute dermal toxicity study was also conducted as per the OECD guidelines 402. The mechanism of drug release followed Korsemeyer–Peppa’s model. The optimized batch showed a pH range from 6.867 ± 0.015 to 6.91 ± 0.254, drug content 94.6% ± 0.686% w/w of the active principle when studied in triplicate for drug content analysis, the measured viscosity of the formulation was 31402.33 ± 149.0783 mPaS exhibiting a shear thinning system along with thixotropic behavior at 25°C, and sustained drug release of 78% in 8 hours. An ex vivo permeation study demonstrated that 203.73 μg/ml/cm2 drug permeated through skin in 24 hours. Application of aloe emodin-loaded topical hydrogel to psoriatic skin resulted in a reduction of epidermal thickness, scaling, and ear thickness. The key inflammatory marker tissue necrosis factor (TNF-α) also showed a significant decrease. Compared with the marketed formulation, the test formulation showed no significant difference in the percentage reduction in ear thickness. No acute dermal toxicity was observed at the initial dose of 200 mg. The outcome suggests the promising potential of aloe emodin-loaded hydrogel in improving plaque-like psoriasis without dermal toxicity. Further studies are warranted to establish its efficacy in the management of psoriasis.

Ameliorating effects of Acacia arabica and Ocimum basilicum on acetic acid-induced ulcerative colitis model through mitigation of inflammation and oxidative stress

IntroductionUlcerative colitis (UC) is a chronic recurrent inflammatory disease of the large intestine and rectum. The disease is characterized by oxidative stress and severe inflammation. Research has shown the anti-oxidative and anti-inflammatory effects induced by consuming the Acacia arabia and Ocimum basilicum. The present study aimed to evaluate the effect of treatment with O. basilicum together with A. arabica on healing, inflammation, and oxidative stress in the course of experimental colitis in rats. MethodsA total number of 50 male rats were selected and randomly assigned to five groups of 10 rats each. Colitis was induced in rats by enemas with a 4 % acetic acid solution. Four days after the colitis induction, the rats were orally treated for the next 4 days with saline or a combination of A. arabica and O. basilicum (1000 mg/kg) or sulfasalazine (100 mg/kg). ResultsAcetic acid-induced colitis increased the colon's macroscopic and histopathological damage scores; increased colon levels of MDA (Malondialdehyde), MPO (Myeloperoxidase), TNF-α (Tissue necrosis factor α), IL6 (Interleukin 6), and IL17 (Interleukin 17); and decreased SOD (Superoxide Dismutase), GPx (Glutathione Peroxidase), and IL10 (Interleukin 10) levels in the treated rats compared with the control group (P < 0.001). Overall, a combination of A. arabica and O. basilicum reduced macroscopic and histopathological damage scores (P < 0.01) of the colon, and MDA, MPO, TNF-α, IL6 (P < 0.001), and IL17 (P < 0.01) levels of the colon. Furthermore, it increased SOD, GPx, and IL10 levels compared to the colitis group (P < 0.01). ConclusionA. arabica and O. basilicum have improving effects on UC by reducing inflammation and oxidative stress.

Leukocyte-Rich Platelet-Rich Plasma Is Predominantly Anti-inflammatory Compared With Leukocyte-Poor Platelet-Rich Plasma in Patients With Mild-Moderate Knee Osteoarthritis: A Prospective, Descriptive Laboratory Study

Background: Platelet-rich plasma (PRP) has been used extensively in clinical practice to treat patients with symptomatic knee osteoarthritis (OA). Leukocyte-poor PRP (LP-PRP) has been clinically preferred over leukocyte-rich PRP (LR-PRP); however, it is unclear which cytokine mediators of pain and inflammation are present in LR-PRP and LP-PRP from patients with mild to moderate knee OA in order to rationalize a specific formulation. Hypothesis: LP-PRP would be predominantly anti-inflammatory and have reduced nociceptive pain mediators compared with LR-PRP from the same individual with mild to moderate knee OA. Study Design: Controlled laboratory study. Methods: A total of 24 unique samples of PRP were prepared in order to assess 48 samples of LR-PRP and LP-PRP taken from 12 patients (6 male and 6 female) with symptomatic knee OA of Kellgren-Lawrence grade 2 to 3. Patients underwent blood collection for LR-PRP and LP-PRP preparation through a double-spin protocol to obtain baseline whole blood, platelet concentration, and white blood cell subtypes. LR-PRP and LP-PRP from the same patient were produced at the same time and underwent a comprehensive panel through Luminex (multicytokine profiling) to assess key mediators of inflammation: interleukin 1 receptor antagonist (IL-1Ra), interleukin 4, 6, 8, and 10 (IL-4, IL-6, IL-8, and IL-10), IL-1β, tissue necrosis factor α (TNF-α), and matrix metalloproteinase 9 (MMP-9). To assess mediators of nociceptive pain, nerve growth factor (NGF) and tartrate resistant acid phosphatase 5 (TRAP5) were also assessed. Results: LR-PRP from patients with mild to moderate knee OA expressed significantly more IL-1Ra, IL-4, IL-8, and MMP-9 compared with LP-PRP formulations from the same patients. No significant differences were found between LR-PRP and LP-PRP in mediators of nociceptive pain—namely, NGF and TRAP5. Other mediators including TNF-α, IL-1β, IL-6, and IL-10 were also found to have no significant expression differences between LR-PRP and LP-PRP. Conclusion: LR-PRP expressed significantly more IL-1Ra, IL-4, and IL-8, suggesting that LR-PRP may be more anti-inflammatory than LP-PRP. MMP-9 was expressed in higher concentrations in LR-PRP, suggesting that LR-PRP may be more chondrotoxic than LP-PRP. Clinical Relevance: LR-PRP was found to have a robust expression of anti-inflammatory mediators compared with LP-PRP and may be beneficial to patients with long-term knee OA where chronic low-grade inflammation is present. Mechanistic clinical trials are needed to elucidate the key mediators in both LR-PRP and LP-PRP to assess their effect on long-term progression of knee OA.

Interferon gamma, interleukin 6 and tissue necrosis factor alpha levels among asymptomatic HIV patients in Benin City, Nigeria.

Morbidity and mortality associated with HIV infection is immune-mediated, and an understanding of HIV immunology will be beneficial in the management of HIV infectionOBJECTIVE: The objective of this research was to measure the levels of TNF-α, IL-6 and IFN-γ in asymptomatic HIV patients and non-HIV subjects, as well as their relationship with CD4 count. Blood samples were collected from 173 subjects, consisting of 125 asymptomatic HIV patients (44 HAART-naïve and 81 on HAART) and 48 non-HIV subjects. The IFN-, IL-6, and TNF- levels in the blood were determined using enzyme-linked immunosorbent assays, and the CD4 count of all participants was determined using flow cytometry. Regardless of treatment status, the IFN-γ levels of non-HIV subjects were significantly higher than those of HIV patients (p< 0.001). The opposite was true for IL-6, as the levels of IL-6 in non-HIV subjects were significantly lower than those in HAART-naïve HIV patients (p< 0.001) and those on HAART (p< 0.01). TNF-α levels did not differ between HIV patients and their non-HIV counterparts. Generally, the levels of these cytokines was not affected (p> 0.05) by immunosuppression (measured by CD4 count < 200 cells/μL) and there was no significant correlation between CD4 count and these cytokines (p> 0.05). In conclusion, asymptomatic HIV infection decreased IFN-γ, increased IL-6, and had no effect on TNF-α levels, regardless of treatment status. Immunosuppression had no impact on these cytokine levels, and there was no relationship between them and CD4 counts.

Effects of systemic Bifidobacterium longum and Lactobacillus rhamnosus probiotics on the ligature-induced periodontitis in rat

Background/purposeProbiotics might be beneficial in preventing periodontitis. Effects of Bifidobacterium and Lactobacillus on periodontitis were examined using the ligature-induced rat model. Materials and methodsThirty-five male Sprague-Dawley rats were divided into control, ligation, Bifidobacterium longum (BL986), Lactobacillus rhamnosus (LRH09), and combination groups. Periodontitis was induced in maxillary second molars. From the day before ligation, phosphate-buffered saline (for control and ligation groups) or probiotics (2 × 109 CFU/g for probiotic groups) were fed daily. On day 8, gingival mRNA expressions for interleukin (IL)-1β, IL-6, tissue necrosis factor (TNF)-α, IL-10, and NF-κB were determined via qPCR. Micro-computed tomography (μCT) and histomorphometry were employed to examine periodontal destruction. ResultsCompared to the ligation group, mRNA of IL-1β, TNF-α, IL-6, and NF-κB in probiotic groups were significantly decreased, but IL-10 was increased. Besides, the IL-10 was more significant in the combination group than in single-use group. Through μCT, the cementoenamel junction (CEJ)-to-bone distance and trabecular separation in combination group were less than that in ligation group, although the bone volume fraction and trabecular number/thickness showed an increase in three probiotic groups. Histopathologically, the combination group had significantly smaller gingival inflammatory cell-infiltrated area and CEJ-to-epithelium distance than the ligation group and the group with BL986 or LRH09. Additionally, the CEJ-to-bone distance was significantly smaller in the combination group than in the ligation and BL986 groups. ConclusionSystemic combination of BL986 and LRH09 had a synergistic effect on enhancing IL-10 and ameliorating the induced experimental periodontitis, although the single-use still presented partially alleviative effects.

Serum Levels of Neopterin, Galectin-3, Tissue Necrosis Factor Alpha, and Interleukin-10 During the Interictal and Attack Periods of Patients with Migraine

Serum Levels of Neopterin, Galectin-3, Tissue Necrosis Factor Alpha, and Interleukin-10 During the Interictal and Attack Periods of Patients with Migraine

Alzheimer’s Disease and Premature Ovarian Insufficiency

Estradiol promotes neuronal growth, transmission, survival, myelinization, plasticity, synaptogenesis, and dendritic branching and it improves cognitive function. Alzheimer’s disease (AD) is characterized by amyloid plaques, neurofibrillary tangles, and the loss of neuronal connection in the brain. Genomic analysis has concluded that hypoestrogenism influences the APOE gene and increases the risk of AD. Premature ovarian insufficiency (POI) is defined as oligo/amenorrhea in women below 40 years of age, low estradiol, and high-gonadotropin levels. Early symptoms and signs of POI must be detected in time in order to prevent subsequent complications, such as Alzheimer’s disease. Meta-analysis has shown favorable effects of estrogen in preventing Alzheimer’s. We measured some of the typical markers of AD in women with POI such as interleukin 6 (IL-6), interleukin 8 (IL-8), tissue necrosis factor α (TNFα), TAU1, TREM2, and amyloid precursor proteins (APP). While FSH, LH, and IL-8 were significantly higher in POI group, compared to controls, testosterone and DHEAS were lower. A significant decrease in IL-6 was found in the POI group during a 6-month therapy, as well as an increase in amyloid precursor proteins. CONCLUSION: Neurological complications of POI, such as declining short-term memory, cognitive function, and dementia, have to be promptly stopped by initiating estro-progestogen therapy in POI. A long-term continuation of the therapy would be strongly advised.

Evaluation of the Effect of Phytocomplex on Chondroprotective Biomarkers in an Experimental Model of Osteoarthritis in Rats

Osteoarthritis (OA) is most prevalent joint disease and major contributor to non-fatal burden in India, with prevalence rates of 22% - 39%. The use of conventional medication can be associated with insufficient clinical management and serious side effects. The present study aims to evaluate the anti-arthritic activity and chondrocytes protection and regeneration potential of Joint Support Product (JSP) in monosodium Iodoacetate induced Osteoarthritis rat model. Pain threshold, knee joint swelling, Blood inflammatory parameters like Tissue necrosis factor, Interlukin-6, Leukotriene B 4, C- reactive protein and arthritic biomarkers Matrix metalloproteinase-13 and Cartilage Oligomeric Matrix Protein, were estimated. Also Radiographic and histopathological evaluation were done to estimate the severity of OA. Treatment of JSP demonstrated significant increase in pain threshold by 68 % and decrease in knee joint swelling by 92 %. The inflammatory markers decreased significantly (p&lt; .00001) after treatment with JSP. The Tissue necrosis factor decreased by 55 %, Interlukin-6 by 61%, Leukotriene B 4 by 57%, C- reactive protein by 69 % and arthritic biomarkers - Matrix metalloproteinase by 88% and Cartilage Oligomeric Matrix Protein by 37% as compared to disease control rats. Also the radiological evaluation and gross histopathology of rats showed improved chondrocytes structure. Thus JSP’s analgesic, anti-inflammatory, chondrocyte regeneration, and chondroprotective properties have therefore demonstrated an anti-arthritic impact.

Deletion of Smad7 Ameliorates Intestinal Inflammation and Contributes to Fibrosis.

Patients suffering from inflammatory bowel diseases (IBDs) express increased mucosal levels of transforming growth factor (TGF)-β compared with non-IBD controls. SMAD7 negatively regulates TGF-β signaling. An earlier study aiming to target Smad7 showed a lack of clinical benefit. It remains unknown whether inhibition of SMAD7 is beneficial in specific settings of IBD. We evaluated the effect of Smad7 deficiency on inflammation, fibrogenesis, and wound healing. For the initiation of fibrosis in Smad7-/- (Smad7Δex-I) CD-1 mice, the dextran sodium sulfate-induced chronic colitis model and the heterotopic transplantation model of fibrosis were used. Wound closure of fibroblasts from Smad7-/- mice was determined using culture inserts and electric cell-substrate impedance sensing in vitro. In dextran sodium sulfate-induced chronic colitis, Smad7 deficiency was associated with ameliorated inflammation, as evidenced by decreased clinical score, histological score, and myeloperoxidase activity. Absence of SMAD7 decreased T-cell accumulation in colonic tissue and tumor necrosis factor (TNF) mRNA expression levels. Smad7-/- mice showed a significant increase in hydroxyproline and collagen content, as well as ColIVa1 mRNA expression. Wild type mice transplanted with terminal ileum from Smad7-/- mice in the heterotopic animal model for intestinal fibrosis showed a significant increase in collagen content and protein expression of α-smooth muscle actin. Smad7 deficiency is associated with a decrease in intestinal inflammation and an increase in fibrosis. Targeting SMAD7 constitutes a potential new treatment option for IBD; progression of disease-associated fibrosis should be considered.

Effect of Particulate Matter on Achilles Tendon Healing: An Experimental Study in Rats

Category: Basic Sciences/Biologics; Ankle; Sports; Trauma Introduction/Purpose: Exposure of particulate matter (PM) has been linked to several diseases including pulmonary, cardiovascular, oncology, neurology system, and etc. Even though tendon injury has become increasingly common recently, there has been no study of relationship between tendon healing and PM. Hence, we performed experimental study in rats to evaluate whether PM has significant effect on tendon healing. We hypothesized that PM exposure may substantially influence Achilles tendon healing. Here, we evaluated whether PM exposure led to deleterious effect on tendon healing in a rat model of Achilles tendon rupture (ATR). Methods: All experiments with rats were approved by the Institutional Animal Care and Use Committee. The Achilles tendons of 20 Sprague-Dawley rats were transected by open tenotomy. The animals were divided into two groups according to exposure of PM 2.5 (particulate matter less than 2.5µm): control group (Non-PM group) or PM exposure group (PM group). 30 minutes of PM inhalational exposure was performed 3 days a week for 6 weeks in closed chamber systems. After 6 weeks, histologic study of lung, laboratory test and enzyme-linked immunosorbent assay (ELISA) of blood samples, histologic study, transmission electron microscopy (TEM) analysis, biomechanical study, RNA sequencing, and western blot analysis of Achilles tendon was performed. Results: Hematoxylin and eosin (H&amp;E) stain of lung tissue in PM group showed inflammation of alveolar wall and increased macrophage. Laboratory test and ELISA of blood samples from PM group showed significantly higher expression of white blood cell count and tissue necrosis factor alpha (TNF-α) than those from non-PM group, respectively. Histologic study of Achilles tendon in PM group exhibited increased lymphocyte and ossification findings with inflammatory change of cell morphology. TEM analysis showed decreased collagen fibril in PM group than non-PM group. Load to failure was decreased in the PM group than non-PM group. RNA sequencing and ingenuity pathway analysis showed increased cAMP-PKA-CREB signal pathway in PM group and the results were consistent with western blot outcomes. Conclusion: Achilles tendon healing was substantially affected by the PM exposure. Based on the present data, PM exposure induces detrimental histological and biomechanical results on Achilles tendon healing through cAMP-PKA-CREB pathway. Further in-vitro study and larger in-vivo study with longer time period are needed to support the present data.

The effect of combining basil seeds and gum Arabic on the healing process of experimental acetic acid-induced ulcerative colitis in rats

Background & aimUlcerative colitis (UC) is a chronic recurrent inflammatory disease of the large intestine and rectum that oxidative stress and severe inflammation are the main features of this disease. Previous studies have shown that separate consumption of basil and gum arabic can reduce inflammation and oxidative stress. The aim of the study was evaluating the effect of treatment with basil seeds given together with gum arabic on healing, inflammation and oxidative stress in the course of experimental colitis in rats. Experimental procedureA total number of 50 male rats were used, randomly assigned to five groups of 10 rats each. Colitis was induced in rats by enemas with 4% solution od acetic acid. Four days after induction of colitis, rats were treated for next 4 days with saline or combination of basil seeds plus gum arabic (1 mg/kg) or sulfasalazine (100 mg/g) rectally. The experiment was terminated after last dose of treatment. Rats without induction of colitis were used as a sham group. ResultsAcetic acid-induced colitis increased the macroscopic and histopathological damage scores of the colon as well as colon levels of MDA(Malondialdehyde), MPO(Myeloperoxidase), TNFα(Tissue necrosis factor α), IL6 (Interleukin 6)and IL17(Interleukin 17) and decreased SOD(Superoxide Dismutase), GPx (Glutathione Peroxidase) and IL10 (Interleukin 10) levels compared with the control group(P < 0.001). Treatment with basil and gum arabic reduced macroscopic and histopathological damage scores (P < 0.01) of the colon, MDA, MPO, TNFα, IL6(P < 0.001) and IL17 (P < 0.01) levels of the colon and increased SOD, GPx and IL10 levels compared to the colitis group (P < 0.01). ConclusionRectal administration of combination of basil seeds plus gum arabic after induction of colitis, exhibits antioxidant and anti-inflammatory effects, and accelerates the healing of the colon in experimental colitis evoked by acetic acid.

Characterization of transcriptome diversity and in vitro behavior of primary human high-risk breast cells

Biology and transcriptomes of non-cancerous human mammary epithelial cells at risk for breast cancer development were explored following primary isolation utilizing conditional reprogramming cell technology from mastectomy tissue ipsilateral to invasive breast cancer. Cultures demonstrated consistent categorizable behaviors. Relative viability and mammosphere formation differed between samples but were stable across three different mammary-specific media. E2F cell cycle target genes expression levels were positively correlated with viability and advancing age was inversely associated. Estrogen growth response was associated with Tissue necrosis factor signaling and Interferon alpha response gene enrichment. Neoadjuvant chemotherapy exposure significantly altered transcriptomes, shifting them towards expression of genes linked to mammary stem cell formation. Breast cancer prognostic signature sets include genes that in normal development are limited to specific stages of pregnancy or the menstrual cycle. Sample transcriptomes were queried for stage specific gene expression patterns. All cancer samples and a portion of high-risk samples showed overlapping stages reflective of abnormal gene expression patterns, while other high-risk samples exhibited more stage specific patterns. In conclusion, at-risk cells preserve behavioral and transcriptome diversity that could reflect different risk profiles. It is possible that prognostic platforms analogous to those used for breast cancer could be developed for high-risk mammary cells.

Amyloid processing in COVID-19-associated neurological syndromes.

SARS‐CoV‐2 infection can damage the nervous system with multiple neurological manifestations described. However, there is limited understanding of the mechanisms underlying COVID‐19 neurological injury. This is a cross‐sectional exploratory prospective biomarker cohort study of 21 patients with COVID‐19 neurological syndromes (Guillain–Barre Syndrome [GBS], encephalitis, encephalopathy, acute disseminated encephalomyelitis [ADEM], intracranial hypertension, and central pain syndrome) and 23 healthy COVID‐19 negative controls. We measured cerebrospinal fluid (CSF) and serum biomarkers of amyloid processing, neuronal injury (neurofilament light), astrocyte activation (GFAp), and neuroinflammation (tissue necrosis factor [TNF] ɑ, interleukin [IL]‐6, IL‐1β, IL‐8). Patients with COVID‐19 neurological syndromes had significantly reduced CSF soluble amyloid precursor protein (sAPP)‐ɑ (p = 0.004) and sAPPβ (p = 0.03) as well as amyloid β (Aβ) 40 (p = 5.2 × 10−8), Aβ42 (p = 3.5 × 10−7), and Aβ42/Aβ40 ratio (p = 0.005) compared to controls. Patients with COVID‐19 neurological syndromes showed significantly increased neurofilament light (NfL, p = 0.001) and this negatively correlated with sAPPɑ and sAPPβ. Conversely, GFAp was significantly reduced in COVID‐19 neurological syndromes (p = 0.0001) and this positively correlated with sAPPɑ and sAPPβ. COVID‐19 neurological patients also displayed significantly increased CSF proinflammatory cytokines and these negatively correlated with sAPPɑ and sAPPβ. A sensitivity analysis of COVID‐19‐associated GBS revealed a non‐significant trend toward greater impairment of amyloid processing in COVID‐19 central than peripheral neurological syndromes. This pilot study raises the possibility that patients with COVID‐19‐associated neurological syndromes exhibit impaired amyloid processing. Altered amyloid processing was linked to neuronal injury and neuroinflammation but reduced astrocyte activation.

Anti-Inflammatory and Anti-oxidant Functions of Cornuside by Regulating NF-[Formula: see text]B, STAT-1, and Nrf2-HO-1 Pathways.

Cornuside (CNS), found in the fruit of Cornus officinalis Seib, is a natural bisiridoid glucoside that possesses therapeutic effects by suppressing inflammation. This study aimed to determine whether CNS could inhibit the inflammatory response induced by lipopolysaccharide (LPS) in human umbilical vein endothelial cells (HUVECs) and mice, as well as to decipher the mechanisms. After activating HUVECs with LPS, the cells were treated with CNS. Cells were then isolated for protein or mRNA assays to analyze signaling and inflammatory molecules. In addition, mice received an intraperitoneal injection of LPS, followed by an intravenously administered dose of CNS. CNS inhibited cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) expressions induced by LPS. CNS decreased phosphorylated signal transducer and activator of transcription 1 (STAT1)-1 by promoting HO-1 expression, inhibiting nuclear factor (NF)-[Formula: see text]B-luciferase activity, and decreasing COX-2/prostaglandin E2 (PGE2) and iNOS/NO. Furthermore, CNS treatment in LPS-activated HUVECs increased the nuclear translocation of nuclear factor erythrocyte 2-related factor 2 (Nrf2) and combined Nrf2 to anti-oxidant response elements and decreased IL-1[Formula: see text] production. Reduced iNOS/NO expression by CNS was restored when HO-1 RNAi inhibited heme oxygenase-1 (HO-1). After CNS treatment in vivo, iNOS levels in lung tissue and tumor necrosis factor (TNF)-[Formula: see text] expression in the bronchoalveolar lavage fluid were significantly decreased. The results indicated that CNS increased HO-1 expression, reduced LPS-activated NF-[Formula: see text]B-luciferase activity, and inhibited iNOS/NO and COX-2/PGE2, all of which contributed to the inhibition of STAT-1 phosphorylation. Thus, CNS can be a potential new substance for treating inflammatory disorders.

URAT1-selective inhibition ameliorates insulin resistance by attenuating diet-induced hepatic steatosis and brown adipose tissue whitening in mice

ObjectiveAccumulating evidence indicates that high uric acid (UA) is strongly associated with obesity and metabolic syndrome and drives the development of nonalcoholic fatty liver disease (NAFLD) and insulin resistance. Although urate transporter-1 (URAT1), which is primarily expressed in the kidneys, plays a critical role in the development of hyperuricemia, its pathophysiological implication in NAFLD and insulin resistance remains unclear. We herein investigated the role and functional significance of URAT1 in diet-induced obese mice. MethodsMice fed a high-fat diet (HFD) for 16–18 weeks or a normal-fat diet (NFD) were treated with or without a novel oral URAT1-selective inhibitor (dotinurad [50 mg/kg/day]) for another 4 weeks. ResultsWe found that URAT1 was also expressed in the liver and brown adipose tissue (BAT) other than the kidneys. Dotinurad administration significantly ameliorated HFD-induced obesity and insulin resistance. HFD markedly induced NAFLD, which was characterized by severe hepatic steatosis as well as the elevation of serum ALT activity and tissue inflammatory cytokine genes (chemokine ligand 2 (Ccl2) and tissue necrosis factor α (TNFα)), all of which were attenuated by dotinurad. Similarly, HFD significantly increased URAT1 expression in BAT, resulting in lipid accumulation (whitening of BAT), and increased the production of tissue reactive oxygen species (ROS), which were reduced by dotinurad via UCP1 activation. ConclusionsIn conclusion, a novel URAT1-selective inhibitor, dotinurad, ameliorates insulin resistance by attenuating hepatic steatosis and promoting rebrowning of lipid-rich BAT in HFD-induced obese mice. URAT1 serves as a key regulator of the pathophysiology of metabolic syndrome and may be a new therapeutic target for insulin-resistant individuals, particularly those with concomitant NAFLD.

Histological Study of the Effect of Aqueous Extract of the Beetle Cocoon on Liver Tissue of Male Mice.

Traditional medicine has been long used to prevent and/or treat diseases worldwide based on a wealth of experiences, principles, and beliefs in different cultures. Among the extracts used in traditional medicine, we can refer to the aqueous beetle cocoon extract of Larinus maculates popularly known as Tihan in Iraq. To determine the histological effect of this extract on mice liver tissue, the animals were assigned to four groups (n=5) treated with (150,200,400) mg/kg of Cocoon aqueous extract of Larinus maculates for 14 days, respectively. Histology and immunohistochemistry test was performed to evaluate changes in liver tissue and tumor necrosis factor alpha(TNF-α) levels.The results showed various pathological dose-depended changes in the liver tissue, including infiltrations, congestion, and vacuolation, along with some dead cells; moreover, necrotic hepatocytes were observed in the liver of highly concentrated treatment group (400 mg kg-1). In addition, the TNF-α level in the liver tissue was elevated by the increased concentration of the extract. The immunohistochemistry result of positive reaction to TNF-α revealed high reaction in the liver tissue of mice treated with 200 mg kg-1 and 400 mg kg-1, as compared to the control group. Furthermore, as evidenced by the obtained results, changes in hepatocytes and the severity of pathological changes in the liver depends on the concentration of the extract of Larinus maculates.

Paradigms in chronic subdural hematoma pathophysiology: Current treatments and new directions.

Chronic subdural hematomas (CSDHs) are an increasingly common pathology encountered in a neurosurgical trauma practice. Although the operative and nonoperative management of CSDH has been studied extensively, the recurrence rate of CSDH remains high, with no significant decrease in recent years. We undertook a detailed assessment of the known pathophysiological mechanisms by which CSDHs recur to improve our ability to treat patients with this disease successfully. In this review of the literature from the PubMed and Scopus databases, we used the search terms "(pathophysiology) AND chronic subdural hematoma [tiab]" to identify pertinent reviews and articles in English. The results demonstrated a complex inflammatory response to subdural blood, which begins with the formation of a collagen neomembrane around the clot itself. Proinflammatory mediators, such as vascular endothelial growth factor, interleukin-6, interleukin-8, tissue necrosis factor α, matrix metalloproteinases, and basic fibroblast growth factor, then contribute to chronic microbleeding by promoting the formation of fragile, leaky blood vessels, and widening of gap junctions of existing vessels. It is evident that the lack of improvement in recurrence rate is due to pathological factors that are not entirely alleviated by simple subdural evacuation. Targeted approaches, such as middle meningeal artery embolization and anti-inflammatory therapies, have become increasingly common and require further prospective analysis to aid in the determination of their efficacy.