Tumor Necrotic Factor-alpha Research Articles

Low Dose Fractionated Radiotherapy Alters Tumor Blood Vessel Morphology, Increases CD3+CD8+ T Cell Infiltration to the Tumor, and Sensitizes Mesothelioma to Immune Checkpoint Blockade

<h3>Purpose/Objective(s)</h3> Radiotherapy is widely used to palliate symptomatic lesions in patients with mesothelioma. However, radiotherapy alone does not improve patient survival. There is currently little published data on radiotherapy and immunotherapy combination in mesothelioma. Here, we aim to optimize a clinically relevant radiotherapy and immunotherapy combination by pre-conditioning tumor microenvironment using low dose radiotherapy for effective immunotherapy responses using mouse model of mesothelioma. <h3>Materials/Methods</h3> Mice were implanted in the flank with 1 × 10^5 murine AB1-HA mesothelioma cells and radiotherapy treatment commenced on day 10 once tumors were approximately 20-30 mm². Treatment was delivered using an X-RAD SmART small animal image-guided precision irradiator at 225 kV X-RAY (HVL 1mm Cu) with a dose rate of 3 Gy/min. Animals were treated with either 0 Gy (sham-irradiation), or as single or multiple doses of either 2 Gy or 6 Gy over the course of five days. Tumors were harvested two weeks following radiotherapy to assess vessel morphology, T cell infiltration by immunohistochemistry and gene expression using RNA-sequencing. In subsequent experiments, the combination of immunotherapy (anti-PD-1 and anti-CTLA-4) with radiotherapy (2 Gy × 5) were administered concurrently and after radiotherapy as one day and six days apart after the final dose. <h3>Results</h3> Radiotherapy did not change the blood vessel density, pericyte coverage and the basement of the blood vessels (collagen-IV) between sham- and radiotherapy treated groups, suggesting the prescribed radiotherapy doses did not damage the blood vessels. Interestingly, the group receiving radiotherapy dose of 2 Gy × 5 had their vessel length and diameter reduced compared with sham-radiotherapy group and these features are similar to normal vessel characteristics. Analysis of tumor tissues revealed significant influx of CD3⁺CD8⁺ T cells following radiotherapy done of 2 Gy × 5 compared with sham radiotherapy group. Gene expression analysis demonstrated inflammatory response gene sets such as type I interferon and tumor necrotic factor-alpha were upregulated in group receiving radiotherapy of 2 Gy × 5, compared with sham radiotherapy group indicating tumor microenvironment may have been an inflamed "hot tumor" following radiotherapy. The combination of anti-PD-1 monotherapy with radiotherapy cured 50 % of the tumor bearing mice. This low cure rate was increased to 100% once dual immunotherapy (anti-PD-1/anti-CTLA-4) was administered concurrently with radiotherapy. All cured mice rejected secondary tumor rechallenge, suggesting cured mice may have developed immunological memory. <h3>Conclusion</h3> Our preliminary finding suggests radiotherapy dose of 2 Gy × 5 was optimal to normalize the tumor blood vessels, increased T cell infiltration, and induced transcriptomic changes associated with inflammatory responses, which may sensitize mesothelioma to immunotherapy. The combination of anti-CTLA-4/anti-PD-1 and radiotherapy were required to achieve 100% cure rate.

Investigation of Natural Compounds for Therapeutic Potential in Streptozotocin-induced Diabetic Neuroinflammation and Neuropathic Pain.

Diabetic neuropathy (DN) is a serious microvascular complication of diabetes mellitus (DM) that impacts the nervous system. Several risk factors are involved in the progression and maintenance of DN-associated pain, such as higher expression of various inflammatory mediators, e.g., tumor necrotic factor-alpha (TNF-α), nuclear factor-kappa B (NF-κB), and cyclo-oxygenase-2 (COX-2). The present research explores the neuroprotective potential of natural isolates, including berbamine, bergapten, and carveol, on the DM-induced neuroinflammation and neurodegeneration that cause neuropathic pain. The study utilized computerized techniques, including computational analysis (a docking assay and a molecular dynamic simulation) before moving to in vivo protocols. Diabetic neuropathy was induced by intraperitonial injection (IP) of streptozotocin (65 mg/kg), and the animal subjects (rats) were kept for 4 weeks for the development of DN. Once diabetic neuropathy was confirmed, the subjects were treated with berbamine, bergapten, and carveol until the sixth week (i.e., 2 weeks of treatment). At the sixth week, the rats were sacrificed, and the sciatic nerve and spinal cord of each was collected for further molecular investigation. Docking and a molecular dynamic simulation (MDS) delivered the information that the natural compounds (berbamine, bergapten, and carveol) were interacting with the selected target protein (i.e., mitogen-activated protein kinase). After IP, it was found that berbamine, bergapten, and carveol had ameliorated mechanical allodynia and thermal hyperalgesia by the 28th day of the study (2 weeks after treatment) without affecting blood glucose levels. Berbamine, bergapten, and carveol markedly elevated the levels of glutathione (GSH) and glutathione s-transferase (GST), in both the sciatic nerve and spinal cord, and also reduced lipid peroxidase (LPO) and nitric oxide (NO). The abovementioned natural isolates reduced pathologic alterations provoked through DN, a finding confirmed through histopathological assays (hematoxylin and eosin staining and immuno-histochemical analysis). Treatment down regulated higher expressions of the inflammatory mediatorcyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and nuclear factor kappa B (NF-κB), as confirmed by ELISA and polymerase chain reaction (PCR). The outcomes of berbamine, bergapten, and carveol are compared with those of pregabalin as a positive control group. Compared to pregabalin, treatment with the aforementioned three natural compounds improved nociception and reduced hyperalgesic effects, and consequently reduced pain perception and inflammation. Our results suggest the mechanism for the neuro-protective impact of berbamine, bergapten, and carveol might possibly be arbitrated via COX-2, TNF-α, and NF-κB, and regulated by mitogen-activated protein kinase, ultimately ameliorating STZ-provoked, DM-induced neuroinflammation and neurodegeneration, and associated neuropathic pain.

The role of some inflammatory markers, cytokins and tumor markers in diagnosis of endometriosis

Endometriosis is a multifactorial disease which etiopathogenesis has not been elucidated. One of the theories of etiopathogenesis is the inflammatory theory. Aims of the study: To develop a practical non-invasive test for the diagnosis of endometriosis by examining some inflammatory markers and cytokines; to compare the highly sensitive C-reactive protein (hsCRP), cytokines (interleukin-6-IL-6 and tumor necrotizing factor alpha) and the tumor marker cancer antigen 125 (CA-125) among healthy patients and patients with endometriosis; to determine the sensitivity and specificity of each biomarker separately in the diagnosis of endometriosis and to determine their role in the diagnosis of endometriosis. Materials and methods: In a prospective study conducted at the University Clinic for Gynecology and Obstetrics, Ss. Cyril and Methodius University in Skopje, North Macedonia 138 patients were included of a reproductive age between 18-50 years (83 with diagnosis endometriosis operated laparoscopically or with laparotomy) and a control group of 55 healthy women, in a period between 01.09.2018 to 01.05.2021. Serum levels of IL-6, TNF-α, hs-CRP and tumor marker CA-125 were evaluated in both groups. Results: Serum levels of CA-125, IL-6 and TNF-α and hs-CRP were significantly higher in patients with endometriosis compared to the control group. The surface under the ROC curve (AUC) for IL-6, CA-125, hs-CRP, and TNF-α has shown that as individual markers they all have a discriminatory capacity to diagnose patients with endometriosis. Conclusions: Results obtained in our study showed statistically significantly higher serum concentrations of CA-125, IL-6 and TNF-α and hs-CRP in patients with endometriosis compared to the control group of patients. However, none of these biomarkers showed a high sensitivity for diagnosis of endometriosis. It is necessary to find a panel combination of biomarkers with a high sensitivity of about 100% that will enable early diagnosis of endometriosis.

Evaluating the role of muscular exercise in modulating the progress of peptic ulcer treated by quercetin or dexilant in male albino rats

Aim of the Work: Study the role of muscular exercise in modulating the progress of peptic ulcer treated by quercetin or dexilant in rats. Methods: 80 male rats divided into 8 equal groups: Control, gastric ulcer non-treated, gastric ulcer with exercise, dexilant treated gastric ulcer, quercetin treated gastric ulcer, dexilant treated gastric ulcer with exercise, quercetin treated gastric ulcer with exercise, quercetin and dexilant treated gastric ulcer groups. At the end, the collected samples were used to analyze PH, total gastric acidity, ulcer index(UI), curative index(CI), heat shock protein 70(HSP70), asymmetric dimethyle arginine(ADMA), tumor necrotic factor alpha(TNFα) levels. Histopathological and immunohistochemical analyses were done. Results: Non-treated group showed significant decrease of gastric levels of pH and CI with significant increase of gastric total acidity, UI, HSP70, ADMA and TNFα. Also, deterioration of histopathological and immunohistochemical expression of Bcl-2 with increase of NF-κB immunohistochemical expression compared to control group.

Gastroprophylactic Effects of p-Cymene in Ethanol-Induced Gastric Ulcer in Rats

The prevalence of gastric ulcers has increased in recent years, mainly because of non-steroidal anti-inflammatory drug utilization. Therefore, the current study investigates the gastroprotective effect of p-Cymene on absolute ethanol-induced acute gastric mucosal hemorrhagic lesions in rats. Thirty Sprague Dawley rats were randomly separated into five groups: normal control, ulcer control, reference, and two experimental groups. The normal and ulcer control groups were orally fed with 0.5% carboxymethylcellulose (CMC). The reference group was fed orally with 20 mg/kg omeprazole. The experimental groups were fed with 30 mg/kg and 60 mg/kg p-Cymene, respectively. After one hour, the normal group was fed with 0.5% CMC, and groups 2–5 were given absolute alcohol. After another hour all rats were sacrificed. The ulcer control group showed severe superficial hemorrhagic gastric mucosal lesions with decreased gastric mucus secretion and pH of gastric content. p-Cymene significantly reduced ethanol-induced gastric lesions, as evidenced by increased mucus and pH of gastric content, decreased ulcer area, reduced or absence of edema, and leucocyte infiltration of the subcutaneous layer. In gastric mucosal homogenate, p-Cymene displayed a significant increase in superoxide dismutase (SOD), catalase (CAT) activities, prostaglandin E2 (PGE2), and significantly reduced the malondialdehyde (MDA) level. In addition, p-Cymene increased the intensity of periodic acid–Schiff (PAS) stain of the gastric epithelium, and produced up-regulation of the HSP 70 protein and down-regulation of the Bax protein of the stomach epithelium, as well as a reduction in the levels of tumor necrotic factor-alpha and interleukin-6, while the level of interleukin-10 was increased. p-Cymene decreased the level of TNF-a and IL-6, and increased the level of IL-10. Acute toxicity with a higher dose of 500 mg/kg p-Cymene did not manifest any toxicological signs in rats and could enhance defensive mechanisms against gastric mucosal lesions. p-Cymene showed gastroprotective effects that could be attributed to its antioxidant nature, or its ability to increase mucus secretion, increase endogenous enzymes (SOD, CAT, PGE2), reduce MDA level, up-regulate HSP 70 protein, down-regulate Bax protein, and modulate inflammatory cytokines.

Synergistic interaction between acetaminophen and L-carnosine improved neuropathic pain via NF-κB pathway and antioxidant properties in chronic constriction injury model.

BackgroundInflammation is known to underlie the pathogenesis in neuropathic pain. This study investigated the anti-inflammatory and neuroprotective mechanisms involved in antinociceptive effects of co-administration of acetaminophen and L-carnosine in chronic constriction injury (CCI)-induced peripheral neuropathy in male Wistar rats.MethodsFifty-six male Wistar rats were randomly divided into seven experimental groups (n = 8) treated with normal saline/acetaminophen/acetaminophen + L-carnosine. CCI was used to induce neuropathic pain in rats. Hyperalgesia and allodynia were assessed using hotplate and von Frey tests, respectively. Investigation of spinal proinflammatory cytokines and antioxidant system were carried out after twenty-one days of treatment.ResultsThe results showed that the co-administration of acetaminophen and L-carnosine significantly (P < 0.001) increased the paw withdrawal threshold to thermal and mechanical stimuli in ligated rats compared to the ligated naïve group. There was a significant (P < 0.001) decrease in the levels of nuclear factor kappa light chain enhancer B cell inhibitor, calcium ion, interleukin-1-beta, and tumour necrotic factor-alpha in the spinal cord of the group coadministered with acetaminophen and L-carnosine compared to the ligated control group. Co-administration with acetaminophen and L-carnosine increased the antioxidant enzymatic activities and reduced the lipid peroxidation in the spinal cord.ConclusionsCo-administration of acetaminophen and L-carnosine has anti-inflammatory effects as a mechanism that mediate its antinociceptive effects in CCI-induced peripheral neuropathy in Wistar rat.

Quercetin-Rich Ethanolic Extract of Polygonum odoratum var Pakphai Leaves Decreased Gene Expression and Secretion of Pro-Inflammatory Mediators in Lipopolysaccharide-Induced Murine RAW264.7 Macrophages.

Polygonum odoratum var. Pakphai has been used in traditional Thai medicine for the treatment of flatulence and constipation and to relieve the inflammation caused by insect bites. Quercetin (Q), which is abundant in plant-based foods, has been found to exert anti-inflammatory properties. This study evaluated the anti-inflammatory activity of P. odoratum ethanolic extract in RAW264.7 macrophage cells. Leaves were extracted with 50% ethanol, phenolics and flavonoids were then analyzed using UHPLC-QTOF-MS and HPLC-DAD. RAW264.7 cells were induced with lipopolysaccharides (LPSs). They were then treated with the extract and prostaglandin E2 (PGE2), and interleukin-6 (IL-6) and tumor necrotic factor-alpha (TNF-α) concentrations were determined. Levels of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), IL-6 and TNF-α mRNAs were analyzed using qRT-PCR. Chemical analysis demonstrated that the extract was abundant with Q while also containing catechin, gallic acid, epicatechin gallate and coumarin. The extract increased the viability of RAW264.7 cells and dose-dependently decreased nitric oxide production, PGE2, IL-6 and TNF-α levels in the medium from the LPS-induced RAW264.7 cell culture. Consistently, COX-2, iNOS, IL-6 and TNF-α mRNA levels were decreased in a concentration-dependent manner (p < 0.05). Thus, the quercetin-rich ethanolic extract derived from P. odoratum var Pakphai leaves can exert anti-inflammatory activity in LPS-induced RAW264.7 cells through a reduction of the pro-inflammatory mediator response.

Countermeasure efficacy of apigenin for silicon-ion-induced early damage in blood and bone marrow of exposed C57BL/6J mice

We investigated the countermeasure efficacy of apigenin (AP), given as a diet supplement, for radiation-induced damage in the hematopoietic tissues collected on day 7 after a total-body exposure of male C57BL/6J mice to 0 or 0.5 Gy of 260 MeV/n silicon (28Si) ions. We gave food with AP at the concentration of 20 mg/kg body weight (bw) (AP20) or without AP (AP0) to mice before and after irradiation. There were four groups of mice (six mice in each): Group 1- Control, i.e. No Radiation (0 Gy) with AP0; Group 2 - Radiation (0.5 Gy) with AP0; Group 3 - No Radiation (0 Gy) with AP20; and Group 4 - Radiation (0.5 Gy) with AP20. The complete blood count (CBC) and differential blood count were performed for each mouse. In the same mouse, an anti-clastogenic activity of AP was evaluated using the in vivo blood-erythrocyte micronucleus (MN) assay. Further in each mouse, bone marrow (BM) cells were collected and used for measuring the levels of activated nuclear factor-kappa B (NF-κB), and pro-inflammatory cytokines (i.e. tumor necrotic factor-alpha (TNF-α), interleukin-1α (IL-1α), IL-1 beta (IL-1β), and IL-6). We used the colony-forming unit assay (CFU-A) as a tool to study the countermeasure efficacy of AP against the harmful effects of 28Si ions on the proliferation of the hematopoietic stem/progenitor cells (HSPCs). Our results showed that AP is highly effective not only in the prevention of leukopenia and thrombocytopenia but also in the enhancement of erythropoiesis and the proliferation of HSPCs. We also observed the potent anti-clastogenic activity of AP given to mice as a diet supplement. Further, we found that AP is very effective in the suppression of activated NF-κB and pro-inflammatory cytokines, suggesting that AP given as a diet supplement protects mice from 28Si-ion-induced damage in the hematopoietic tissues of irradiated male C57BL/6J mice via its anti-inflammation activity.

Histopathological, Immunohistochemical, And Molecular Alterations In Brain Tissue And Submandibular Salivary Gland Of Atrazine-Induced Toxicity In Male Rats.

Atrazine (ATZ) is herbicide that has been widely used for different crops. This extensive use has resulted in severe deleterious effects in different species. In this work, we investigated the potentially harmful effect of atrazine herbicide on the brain and submandibular salivary gland. Our investigation was carried out on 20 adult male albino rats that were equally divided into two groups. The first group received distilled water as control, while the second group received ATZ at 200mg/kg body weight/ day via stomach gavage for 30 successive days of the experiment; the oral LD50 for ATZ is 3090mg/kg. Our findings revealed the ability of ATZ to cause damage to the cerebrum, hippocampus, and submandibular salivary gland. This damage resulted from the induced oxidative stress, which was indicated by a significant elevation in malondialdehyde (MDA) concentration, DNA fragmentation, tumor necrotic factor-alpha (TNF-α) expression, with a significant decrease in reduced glutathione (GSH) level and reduction of B cell lymphoma 2 (BCL2), dopamine receptor D1 (Drd1), cAMP-responsive element-binding protein 1 (Creb1) genes expression after ATZ exposure. Moreover, degeneration of cells, cytoplasmic vacuolation, congestion of blood vessels, a strong immune reaction to caspase 3, and negligible immune expression of a glial fibrillary acidic protein (GFAP) were also noticed in the ATZ-treated group. We concluded that ATZ induces oxidative stress and has a toxic and apoptotic effects on the cerebrum, hippocampus, and salivary gland of adult male albino rats.

Neuroprotective effects of Lippia javanica (Burm.F.) Spreng. Herbal tea infusion on Lead-induced oxidative brain damage in Wistar rats

BackgroundThough Lippia javanica (Burm.f.) Spreng antioxidant activity has been demonstrated, its effect in protecting the brain from lead (Pb)-induced oxidative damage is unknown. This study investigated the effect of L. javanica against Pb-induced oxidative stress, inflammation, apoptosis and acetylcholinesterase activity in rat’s brain.MethodsL. javanica herbal tea infusion was prepared, its phytochemical constituent was revealed by liquid chromatography-Mass spectrometer (LC-MS) and was administered simultaneously with Pb. Four groups of male Wistar rats (n = 5/group) were used: control received distilled water; Pb-acetate group received 50 mg Pb/ Kg bodyweight (bw), treatment group received 50 mg Pb/ Kg Pb-acetate + 5 ml/kg bw L. javanica and L. javanica group received 5 ml/Kg bw of L. javanica tea infusion only. After 6 weeks of treatment, oxidative status, acetylcholinesterase activity, inflammation and apoptosis was assessed in brain tissue which was also histologically examined.ResultsMean brain and heart weight was reduced (p < 0.05) while liver and spleen weights were increased (p < 0.05) in Pb exposed animals but were prevented by L. juvanica treatment. Treatment with L. javanica increased (p < 0.05) overall brain antioxidant status (glutathione and superoxide dismutase activities) and reduced lipid peroxidation (p < 0.05) compared to the Pb exposed animals. Pro-inflammatory cytokine tumour necrotic factor-alpha, pro-apoptosis Bax protein and anticholinesterase activity were reduced (p < 0.05) in Pb-L. javanica treated animals compared to the Pb exposed group. Histological examination confirmed neuroprotective effects of L. javanica as evidenced by reduced apoptosis/necrosis and inflammation-induced vacuolization and oedema in the hippocampus. The L. javanica treatment alone had no detrimental effects to the rats. LC-MS analysis revealed L. javanica to be rich in phenolics.ConclusionsThis study demonstrated that L. javanica, rich in phenolics was effective in reducing Pb-induced brain oxidative stress, inflammation, apoptosis, acetylcholinesterase activity and neuronal damage.

Serum Interleukin-6 Level Raise Up In Time With Muscle Soreness at 24 Hours Recovery From Vigorous Exercise: Does It Correlate ?

Background : Muscle soreness or muscle pain occurs after long-term physical activity or after unusual exercise. Some explains it due to pro inflammatory cytokines secreted during and after exercise. Interleukin-6 and tumor necrotic factor alpha were two cytokines believed as promoting factor of muscle soreness. Until now, it was still unclear whether interleukin-6 or tumour necrotic factor alpha that correlate with the soreness found at 24 hours recovery from vigorous exercise. Purpose : This study was aimed to analyse the level of interleukin-6 and tumour necrotic factor alpha by time of 6- and 24-hour recovery from exercise. Method/Material: Correlation study research method with a cross-sectional research design. The subject of this study were twenty voluntary trained, healthy male, aged 20-30 years old with normal body mass index was randomly registered in this study. Subjects was grouped in vigorous exercised group and moderate exercised group as control. The blood was obtained from the subjects at 6 and 24 hours recovery post exercise for interleukin-6 and tumor necrotic factor alpha level measurement. Result : Was shown raised of pain intensity of muscle soreness and interleukin-6 level but not tumor necrotic alpha level. The interleukin-6 level correlated to the pain intensity of muscle soreness at 24 hours post exercise (P<0,05).

Comparative evaluation of microRNA-155 expression level and its correlation with tumor necrotizing factor α and interleukin 6 in patients with chronic periodontitis

MicroRNAs are a class of small noncoding ribonucleic acids that perform a critical role in adjustment of gene expression. miRNAs-155 (miR-155) participates in controlling inflammation. Periodontitis is defined as inflammatory disorder of tissues surrounding the teeth. In this study, the expression levels of miR-155 and its target genes, tumor necrotizing factor alpha (TNF-α), and interleukin-6 (IL-6) were evaluated in a group of Iranian patients. This sectional study was performed on 10 healthy controls and 10 individuals with chronic periodontitis by means of polymerase chain reaction (PCR) test. For each individual, clinical parameters including probing depth and clinical attachment loss and blood samples were measured. Levels of miR-155, TNF-α, and IL-6 were quantified using real-time PCR (α=0/05) and the results were analyzed by Mann-Whitney U test. The level of miR-155 was significantly higher in patients with chronic periodontitis (P < 0.001). A positive correlation was observed between the level of miR-155 and clinical parameters (P < 0.05). Level of miR-155 in tissue samples was correlated with blood samples although the expression level was higher in blood samples. As the expression level of miR-155, TNF-α, and IL-6 genes was higher in subjects with chronic periodontitis than healthy individuals, it might suggest a role for miR-155 in patients with chronic periodontitis.

L-Methionine inhibits 4-hydroxy-2-nonenal accumulation and suppresses inflammation in growing rats.

4-Hydroxy-2-nonenal (HNE) is a biomarker for oxidative stress to induce inflammation. Methionine is an essential sulfur-containing amino acid with antioxidative activity. On the other hand, the evidence on whether and how methionine can depress HNE-derived inflammation is lacking. In particular, the link between the regulation of the nuclear factor-κB (NF-κB) signaling pathway and methionine intake is unclear. This study examined the link between depression from HNE accumulation and the anti-inflammatory function of L-methionine in rats. Male Wistar rats (3-week-old, weighing 70-80 g) were administered different levels of L-methionine orally at 215.0, 268.8, 322.5, and 430.0 mg/kg body weight for two weeks. The control group was fed commercial pellets. The hepatic HNE contents and the protein expression and mRNA levels of the inflammatory mediators were measured. The interleukin-10 (IL-10) and glutathione S-transferase (GST) levels were also estimated. Compared to the control group, hepatic HNE levels were reduced significantly in all groups fed L-methionine, which were attributed to the stimulation of GST by L-methionine. With decreasing HNE levels, L-methionine inhibited the activation of NF-κB by up-regulating inhibitory κBα and depressing phosphoinositide 3 kinase/protein kinase B. The mRNA levels of the inflammatory mediators (cyclooxygenase-2, interleukin-1β, interleukin-6, inducible nitric oxide synthase, tumor necrotic factor alpha) were decreased significantly by L-methionine. In contrast, the protein expression of these inflammatory mediators was effectively down regulated by L-methionine. The anti-inflammatory action of L-methionine was also reflected by the up-regulation of IL-10. This study revealed a link between the inhibition of HNE accumulation and the depression of inflammation in growing rats, which was attributed to L-methionine availability. The anti-inflammatory mechanism exerted by L-methionine was to inhibit NF-κB activation and to up-regulate GST.

Insulin resistance; mechanisms and related health hazards: a review article

Insulin resistance (IR) is related to metabolic syndrome, which is manifested by biochemical and physical disturbances that could be related to increased weight, atherogenic dyslipidemia, pro-inflammatory conditions, pro-thrombotic conditions, and hypertension. The process is complex, and the operating mechanisms are not well understood. Thus, this article aimed to determine the mechanisms of IR and its related serious health problems. It was found that subjects with impaired glucose-6-phosphate action and muscle glycogen production carry a 40% chance of developing type-2 diabetes mellitus. Further, the pro-inflammatory mediator interleukin-6 (IL-6) increases the insulin-induced glucose take-up by myocytes and decreases IR or increases insulin sensitivity in the entire body. Many reports documented an increase in IL-6 in the skeletal muscles of obese people. Cultured myocytes from obese diabetic individuals produce more monocyte chemo-attractant protein 1 and tumor necrotic factor alpha (TNF-α). TNF-α could affect mitochondrial function in myocytes and stimulate IR. The binding of insulin to the insulin receptors on endothelial cells activates the mitogen-activated protein kinase and the phosphatidylinositol 3-kinase pathways. In contrast to the first pathway, the second pathway is pro-atherogenic and is activated by IR. It was concluded that IR is associated with increased release of pro-inflammatory mediators, oxidative stress molecules, and modulation of insulin receptors in fatty tissues and endothelial cells.

Acetyl-L-Carnitine protects against LPS induced depression via PPAR-γ induced inhibition of NF-κB/NLRP3 pathway

IntroductionMajor depressive disorder (MDD) is a debilitating human health status characterized by mood swings and high suicidal attempts. Several studies have reported the role of neuroinflammation in MMD, yet the efficacy of natural drug substances on neuroinflammation-associated depression needs to be further investigated. The present study demonstrated the neuroprotective effects of Acetyl-L- carnitine (ALC) alone or in combination with caffeic acid phenethyl ester (CAPE) on lipopolysaccharide (LPS) induced neuro-inflammation, depression, and anxiety-like behavior.Material and methodsMale Sprague Dawley (SD) rats were used to explore the relative effects of ALC and the mechanistic interplay of the peroxisome proliferator-activated receptors (PPARγ) in depression. Lipopolysaccharide (LPS) was administered to induce depression and anxiety-like symptoms such as a decreased grooming tendency, diminished locomotive activity, and increased immobility period.ResultsWe found marked neuronal alterations in the cortex and hippocampus of LPS intoxicated animals associated with higher inflammatory cytokines expression cyclooxygenase (COX2), tumor necrotic factor-alpha (TNF-α). These detrimental effects exacerbate oxidative stress as documented by a compromised antioxidant system due to high lipid peroxidase (LPO). ALC significantly reverted these changes by positively modulating the PPARγ dependent downstream antioxidant and anti-inflammatory pathways such as NOD and pyrin domain-containing protein 3 (NLRP3) linked nuclear factor kappa B (NF-κB) phosphorylation. Moreover, co-administering NF-κB inhibitor caffeic acid phenethyl ester (CAPE) with ALC also increased PPARγ expression significantly and decreased NF-ᴋB and NLRP3 inflammasome.ConclusionsThese findings indicate that ALC could be a possible depression supplement. The effects are partly mediated by inhibiting neuroinflammation and NLRP3 inflammasome coupled to PPARγ upregulations.

Plasma cytokines quantification among Trypanosoma brucei rhodesiense sleeping sickness cases and controls in Rumphi, Malawi.

Trypanosoma brucei (T.b.) rhodesiense is the cause of the acute form of human African trypanosomiasis (HAT) in eastern and southern African countries, including Malawi. For a long time, untreated HAT infections were believed to be 100% fatal. However, recent studies show that infection by T.b. rhodesiense can result in a wide range of clinical outcomes in its human host. Apart from other factors such as parasite diversity, cytokines have been strongly implicated to play a major role in the outcome of T.b. rhodesiense infections.In this study, we quantify the levels of three cytokines Interleukin-8 (IL-8), Tumor Necrotic Factor alpha (TNF-α) and Interleukin -10 (IL-10) in plasma amongst HAT cases (treated and untreated) and controls recruited during medical survey. Two-hundred and thirty-three plasma samples (HAT cases and controls) from Rumphi, one of the endemic areas in Malawi were used. Blood collected was centrifuged, plasma extracted and stored in cryovials at -80°C until processing. Plasma cytokine concentration was measured using ELISA. Plasma samples for 233 individuals, 76 HAT cases and 157 controls were quantified. Among the cases, nine had their plasma collected before treatment (untreated) and the rest were treated before blood for plasma analysis was collected. Controls had significantly higher mean plasmatic levels of TNF-α (94.5 ±474.12 pg/ml) and IL-8 (2258.6 ±5227.4 pg/ml) than cases TNF-α (29.35±181.58 pg/ml) and IL-8 (1191.3±4236.09 pg/ml). Controls and cases had similar mean levels of IL-10 in plasma. Only IL-8 had statistically significant higher median levels in the untreated than treated HAT cases P=0.006. Our data suggest that cytokines could be considered as biomarkers of HAT infection and treatment. Further studies with a larger cohort of cases and additional cytokines which are known to be associated with HAT infection outcomes will be required to evaluate these cytokines further.

Effects of Different Progesterone Doses on the Concentrations of Proinflammatory and Anti-inflammatory Cytokines in Pregnant Women With Threatened Abortion.

Background and objectiveThis study aimed to investigate how different doses of progesterone influence the concentrations of interleukin-6 (IL-6) and tumor necrotizing factor-alpha (TNF-α), which are proinflammatory cytokines, as well as that of IL-10, which is an anti-inflammatory cytokine, in pregnant women with threatened abortion.Materials and methodsThis is a prospective, single-center, randomized controlled trial conducted with 221 patients with a threatened abortion diagnosis. Group 1 consisted of IL-6, IL-10, and TNF-α values in pre-treatment blood samples from 221 patients diagnosed with imminent abortion. Group 2 included 81 patients who received natural oral 100 mg micronized progesterone MP twice a day for two weeks. Group 3 included 83 patients who were administered oral 200 mg of natural micronized progesterone MP twice a day for two weeks. Group 4 included 57 patients who received oral 200 mg of natural micronized progesterone MP twice a day for two weeks, and one depot progesterone was added to the treatment by administering it at a dosage of 500 mg/day intramuscularly.ResultsIL-6 values between groups were lower in group 4 compared to group 3 (p=0.007). When IL-10 values were compared between the groups, the IL-10 ratio was highest in group 4 and lowest in group 2 (p<0.001, p=0.003, p<0.001). When the TNF-α values between the groups were compared, the value in group 4 was decreased compared to groups 1 and 2 (p=0.031, p<0.001). In the logistic regression analysis, the IL-6 value above 12.01 increased the abortion imminens rate 1.01 times, and a TNF-α value above 11.04 increased the abortion imminens rate 1.21 times.ConclusionProgesterone used to treat imminent abortion reduces the levels of proinflammatory cytokines, such as IL-6 and TNF-α, while increasing those of anti-inflammatory cytokine IL-10 in proportion to the dose administered. Progesterone can prevent imminent abortion by generating an anti-inflammatory environment.

Synthesis of silver nanoparticles by Galega officinalis and its hypoglycemic effects in type 1 diabetic rats

Objective(s): Diabetes is related with the higher blood levels of liver enzymes and inflammatory factors. Galega officinalis is used as a medicinal plant for treatment of diabetes traditionally. In this work, silver nanoparticles (Ag-NPs) were synthesized with green method using Galega officinalis extract.Materials and Methods: The synthesized green Ag-NPs were characterized completely. Intact or diabetic rats receieved intraperitoneal injection of saline or 2/5mg/Kg green synthesized Ag-NPs. Mean serum levels of glucose, hepatic enzymes and hematological parameter were determined. Gene expression of tumor necrotic factor alpha (TNF-α) was done by real-time PCR. Results: Synthesis of green synthesized Ag-NPs was confirmed by FT-IR, XRD and UV-vis analyses. The FESEM and TEM images showed spherical Ag-NPs with size of 25 nm. The hypoglycemic influence of Ag-NPs using Galega officinalis extract is reported for the first time in this study. Blood concentration of liver enzymes, urea, glucose, white blood cells count and TNF-α mRNA levels in visceral adipose tissue significantly declined in diabetic rats receiving Ag-NPs.Conclusion: The synthesized Ag-NPs using Galega officinalis extract may improve complication of diabetes via preventing liver hepatocyte damage and reducing inflammatory factors.

Autoimmune Rheumatic Diseases and Vascular Function: The Concept of Autoimmune Atherosclerosis.

Autoimmune rheumatic diseases (AIRDs) with unknown etiology are increasing in incidence and prevalence. Up to 5% of the population is affected. AIRDs include rheumatoid arthritis, system lupus erythematosus, systemic sclerosis, and Sjögren’s syndrome. In patients with autoimmune diseases, the immune system attacks structures of its own body, leading to widespread tissue and organ damage, which, in turn, is associated with increased morbidity and mortality. One third of the mortality associated with autoimmune diseases is due to cardiovascular diseases. Atherosclerosis is considered the main underlying cause of cardiovascular diseases. Currently, because of finding macrophages and lymphocytes at the atheroma, atherosclerosis is considered a chronic immune-inflammatory disease. In active inflammation, the liberation of inflammatory mediators such as tumor necrotic factor alpha (TNFa), interleukine-6 (IL-6), IL-1 and other factors like T and B cells, play a major role in the atheroma formation. In addition, antioxidized, low-density lipoprotein (LDL) antibodies, antinuclear antibodies (ANA), and rheumatoid factor (RF) are higher in the atherosclerotic patients. Traditional risk factors like gender, age, hypercholesterolemia, smoking, diabetes mellitus, and hypertension, however, do not alone explain the risk of atherosclerosis present in autoimmune diseases. This review examines the role of chronic inflammation in the etiology—and progression—of atherosclerosis in autoimmune rheumatic diseases. In addition, discussed here in detail are the possible effects of autoimmune rheumatic diseases that can affect vascular function. We present here the current findings from studies that assessed vascular function changes using state-of-the-art techniques and innovative endothelial function biomarkers.

Ascorbic Acid Supplementation Attenuates Hippocampal Neuronal Damage in Orchiectomized Rats

Understanding the bidirectional relationship in the cellular and molecular mechanisms associated with testosterone deprivation and cognitive activities has become a high-priority goal. Testosterone has been shown to have effects in the nervous system, ranging from targeting gene expression to modulating neurotransmission. This study therefore evaluated the modulatory role of ascorbic acid in the hippocampus of orchiectomized rats. Twenty-one adult male Wistar rats with an average weight of 170g±10g were randomly assigned into three groups of seven rats each; the control, orchiectomized (orchiectomy+flutamide, 11 mg/kg body weight, bw), and ascorbic acid (orchiectomy+flutamide, 11 mg/kg bw + ascorbic acid, 100 mg/kg bw). Treatment was by oral gavage and lasted for 30 days. Nitrosative stress and neuroinflammatory analysis, hormonal, histological and immunohistochemical expression of astrocytes in the hippocampus were examined. Results showed significantly increased expression of acetylcholinesterase, inducible nitric oxide synthase, and tumour necrotic factor-alpha in the hippocampus of orchiectomized animals. There was altered cytoarchitectural morphology evidenced by reduced Nissl profiles in neuronal axons and dendrites, which corresponded to apoptotic changes, and increased expression of reactive astrocytes suggesting neuronal damage. Nitrosative stress and inflammatory perturbations were well modulated in animals treated with ascorbic acid with unaltered hippocampal morphology. The results indicated that decline in brain androgen activities caused inflammatory and oxidative stress-driven alterations in the hippocampus, while ascorbic acid supplementation offered therapeutic value by modulating neurochemicals and scavenging free radicals in the hippocampus.