Background: Apoptosis disruptions play substantial roles in pathogenesis of arthritis and its symptoms. Cytokines and their intracellular signaling have pivotal roles in arthritis pathophysiology. This study aimed to investigate the relationship between synovial Interleukin-6 (IL-6), nuclear factor kappa-B (NF-ĸ B), and fractalkine (FKN) in the changes of edema and apoptosis during adjuvantinduced knee arthritis. Methods: A total of 240 male Wistar rats were divided into different groups. Arthritis was evoked and the knee edema changes were evaluated by Vernier caliper. Synovial IL-6 was assayed by rat standard ELISA kit. Levels of NF-ĸ B, fractalkine, and apoptotic indicators in the synovium were evaluated by Western blot method. Results were expressed as Mean± SEM. To analyze within-group variations, repeated measures ANOVA, followed by post hoc Tukey’ s test was used (SPSS, 16). Independent samples t test was used to designate significant differences in knee diameter, synovial level of IL-6, apoptotic markers, NF-ĸ B, and FKN between groups. Significance level was set at P≤ 0. 05. Results: The injection of Complete Freund's Adjuvant (CFA) caused intense knee edema (P< 0. 001), which was reduced by implementing anti-IL-6 (P< 0. 001), anti-FKN (P< 0. 001), Inh-NF-ĸ B (P< 0. 001), and anti-FKN+ Inh NF-kB (P< 0. 001). The results indicated elevated levels of apoptotic markers during the acute phase (P = 0. 010), along with an increase in IL-6 (P< 0. 001), NF-ĸ B (P< 0. 001), and FKN (P= 0. 030). Although IL-6 (P< 0. 001), NF-ĸ B (P= 0. 001), and FKN (P= 0. 007) levels elevation continued during the chronic phase, the apoptosis markers decreased in this phase (P= 0. 050). The findings revealed that Anti-IL-6 treatment during different phases of the study could change the synovial NF-ĸ B and FKN. Conclusion: It seems that time-dependent variations in apoptotic markers level may be involved in pathogenesis of adjuvant-induced knee arthritis. In conclusion, synovial IL-6 through NF-ĸ B-FKN pathway can play an important role in this process.

Introduction: Stimulation of peptidergic fibers activates microglia in the dorsal horn. Microglia activation causes fractalkine (FKN) release, a neuron-glia signal, which enhances pain. The transient vanilloid receptor 1 (TRPV1) mediates the release of neuropeptides, which can subsequently activate glia. TRPV1 and TRPV2 are generally expressed on C and A d fibers, respectively. Expression of both proteins is upregulated during inflammation, but expression of TRPV3 after induction of inflammation is unclear.Methods: Adult male Wistar rats were used in all experiments. Arthritis was induced in them by single subcutaneous injection of complete Freund’s adjuvant (CFA) in their right hindpaws. Resiniferatoxin (RTX) was used to eliminate peptidergic fibers. We examined the relation between FKN and TRPV3 expression by administration of anti-FKN antibody.Results: Our study findings indicated that 1) spinal TRPV3 was mostly expressed on nonpeptidergic fibers, 2) expression of spinal TRPV3 increased following inflammation, 3) elimination of peptidergic fibers decreased spinal TRPV3 expression, 4) alteration of hyperalgesia was compatible with TRPV3 changes in RTX-treated rat, and 5) anti-FKN antibody reduced spinal TRPV3 expression.Discussion: It seems that the hyperalgesia variation during different phases of CFA-induced arthritis correlates with spinal TRPV3 expression variation on peptidergic fibers. Moreover, spinal microglial activation during CFA inflammation is involved in TRPV3 expression changes via FKN signaling.

Background: Severe acute pancreatitis (SAP) is a serious systemic disease with high mortality. This study aims to investigate the role of the chemokine, fractalkine (FKN), in the pathogenesis of SAP and the effects of intervention by ulinastatin on FKN expression in an SAP rat model.Methods: We randomly divided 72 Sprague Dawley rats into the following groups: SAP, ulinastatin treatment (UT), and control (C). The SAP model was induced by retrograde infusion of 4% sodium taurocholate into the bili-pancreatic ducts of the rats. Rats in the UT group were injected with ulinastatin immediately after establishment of the SAP model. Serum FKN levels were detected by ELISA at various time points. Histopathological analyses of the pancreas and lung were performed. Expressions of FKN mRNA in the tissues of the pancreas and lung were detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) at various time points for each group.Results: Serum levels of FKN at 3 h after surgery in the SAP subgroup were significantly higher than those in the C group (P<0.05). There were no significant differences between the UT and C groups observed at various time points. Expression levels of FKN mRNA in the pancreatic tissues of the SAP group increased gradually. Although we observed no difference between the SAP and C groups (P>0.05) at 1 hour h after surgery, mRNA levels of FKN in the lung tissues at 3, 6, and 12 h post-surgery in the SAP subgroups were significantly higher than those in the C group for the same time points (P<0.05). Pathological injury of the pancreatic tissues was more remarkable in the SAP group compared to the UT group.Conclusion: FKN may play an important role in the pathogenesis of SAP and SAP-related acute lung injury (ALI). Ulinastatin efficiently interferes with SAP and SAP-related ALI and may be related to inhibition of FKN expression.

Introduction: A variety of molecular pathways, such as generation of advanced glycation end products, inflammation, and oxidative stress, are involved in the development of diabetic nephropathy (DN). Recently, a protective effect of omega-3 polyunsaturated fatty acids on the kidney has been reported. This study aimed to determine serum docosahexaenoic acid (DHA) level and its association with inflammation factors in patients with DN.Materials and Methods: One hundred patients with type 2 diabetic mellitus were divided into 3 groups of non-DN, early DN, and clinical DN, based on 24-hour urinary albumin levels. Hemoglobin A1c, biochemical indicators, b2-microglobulin, and 24-hour urine albumin levels were assessed. Enzyme linked immunosorbent assay was applied to determine the serum concentrations of DHA, advanced glycation end products, fractalkine, superoxide dismutase, and tumor necrosis factor-a.Results: Lower serum DHA and superoxide dismutase and higher serum b2-microglobulin and 24-hour urine albumin levels were associated with clinical DN, compared to no DN and early DN. The reductions in serum DHA levels were different among the patients with early and clinical DN, stratified by sex, body mass index, and serum lipid levels. Serum DHA significantly correlated positively with superoxide dismutase and negatively with fractalkine and tumor necrosis factor-α in the patients with DN.Conclusions: Docosahexaenoic acid may suppress the expression and secretion of fractalkine through inhibiting the tumor necrosis factor-a signaling pathway in DN patients, which improves inflammation and oxidative stress of the kidney, and in turn, delaying the development of DN.

Introduction: Ganoderma resinaceum is used to treat oxidative and inflammatory-related diseases such as cardiovascular and liver diseases. Thus, this study aimed to evaluate the antioxidant and anti-inflammatory activities of different extracts from G. resinaceum fruiting bodies. Methods: Aqueous crude (GRT), mycelial (MYC), exopolysaccharide (EPS I, EPS II) and water-soluble polysaccharide-rich (GRP I and GRP II) extracts of G. resinaceum were assessed for their free radical scavenging and metal chelating ions assays. The in vitro anti-inflammatory activity was evaluated by stabilization of erythrocytes’,membranes and protein denaturation assays. For the in vivo study, paw oedema was induced by administration of κ,-carrageenan (0. 1 mL,1%) to male Wistar rats aged 4 to 6 weeks. Animals were pre-treated with G. resinaceum extracts (125 mg/kg) and diclofenac sodium (20 mg/kg). Inflammatory cytokine and chemokine levels were determined, and histological analysis of paw tissue was performed. Results: G. resinaceum polysaccharide-rich extracts (GRP I and GRP II) showed the best bioactivities. They scavenged DPPH (1, 1-diphenyl-2-picrylhydrazyl, ABTS (2, 2-azino-bis-3-ethylbenzylthiazoline-6-sulfonic acid, and NO (nitric oxide) radicals, and chelated ferrous ions, stabilized murine erythrocyte membranes, and inhibited protein denaturation. At 125 mg/kg, GRP I and GRP II restored the microarchitecture with a weak infiltration of immune cells in the subcutaneous tissues. Moreover, they decreased the overproduction of proinflammatory cytokines growth colony-stimulating factor (G-CSF), interferon gamma (IFNγ, ), tumour necrosis factor alpha (TNFα, ), chemokines (eotaxin, fractalkine) and increased the levels of anti-inflammatory cytokines (IL-10, IL-12p70). Conclusion: G. resinaceum polysaccharide extracts could be potent antioxidant and anti-inflammatory agents.

In daily life, stress in one of the important and potent modulators of behaviour. Inhibitory or faciliatory effects of acute and chronic stress exposure on memory performance (acquisition, consolidation and retrieval) have shown in previous researches. Under such circumstances, the levels of (nor) epinephrine (NE) rapidly increases in the memory related area including hippocampus and amygdala. Along with NE, the hypothalamic-pituitary-adrenocortical axis activates. Glocorticoids (GCs) hormones are the main end-products of the HPA axis activation. In different animal models have been shown that NE and glocorticoids mediate the modulatory effect of stress on memory. Microglia that originally form in the yolk sac are immune cells in the central nervous system and act as the brain's first line of cellular defense against various pathogens. These cells release inflammatory mediators and neurotrophic factors and also phagocytes cellular debris. In addition, are also shown to play a role in the development of brain. During embryonic development, microglia remove apoptotic cells and regulate synaptic pruning. These cells play an essential role in regulating of synapse regeneration, neurogenesis, synaptic function, angiogenesis and myelination. They are dynamic cells in the adult brain and have the ability to rapidly change their morphology to properly respond to the functional needs of the brain. Microglia is activated in M1 and M2 phenotype. M1 microglia activation is induced by gamma interferon and LPS and promotes inflammation via release of inflammatory mediators such as tumor necrosis factor alpha (αTNF) and interleukins. M2 activation mainly is related to secretion of glucocorticoids, extracellular matrix proteins and anti-inflammatory cytokines. It has been reported that microglia as a key regulator of neuronal function have NE and GCs receptors, suggesting a critical role of these brain cells in modulating stress effects. Several lines of studies indicates that microglia regulate learning and memory via the formation and stability of synapses. Microglia actively contribute in synaptic pruning via classical complement cascade mechanism. Apoptotic, immature or poorly growing synapses are labeled with complement components, C1q and C3. Microglia recognize these complement components through the complement receptor CR3 and eliminate C1q and C3-labeled synapses. Microglia also detect and remove inactive synapses by the triggering receptor expressed on myeloid cells 2 (TREM2) consequently regulate brain connectivity and activity. Moreover, microglia regulatory negative feedback mechanism prevents neuron hyperactivity. Microglia play an important role in the stability of long-term potentiation. In addition, microglial fractalkine signaling is potentially involved in LTD. The number and morphology of hippocampal microglia is altered in response to chronic stress exposure thus consequently becomes reactive phenotype. This effect is mediated via stress hormones. Evidence show that stress also affect expression of microglial genes (cytokines, TNF-α and interleukins) that have regulatory role in learning and memory. Microglial–neuronal crosstalk which is crucial for memory processing is another site for stress-induced memory changes. Moreover, stress exposure alters glutamate transmission through negative effect on kynurenine pathway. These effects support the involvement of microglia in destructive effect of stress on memory. In this review article, focusing on newly published articles, we examine the role of microglia in synaptic plasticity, learning and memory, and especially the role of activated microglia in the effects of stress on learning and memory. By examining these processes, our aim is to provide an overview of the role of microglia in synaptic plasticity and learning and memory, and the possibility of using microglia targeting as a therapeutic method to improve cognitive deficits associated with stressful conditions