Inflammation in Focus: The Beginning and the End

The inflammation is an important biological response induced by various harmful stimuli, like viruses, bacterial infections, toxins, toxic compounds, tissue injury. During inflammation inflammatory cytokines and reactive oxygen species are produced. Inflammatory cytokines act on various receptors present on the plasma membrane of target cells. To initiate signaling cascade, and activate transcription factors, receptors should be internalized and enter the early endosomes, where the members of the signaling cascade can meet. The further cytoplasmic fate of the receptor plays crucial role in the progression and the course of inflammation. Usually acute inflammation removes injurious stimuli and helps to regain the normal healthy status of the organism. In contrast to this the uncontrolled chronic inflammation—stimulating other than immune cells, inducing transdifferentiation—can provide base of various serious diseases. This paper draws the attention of the long-lasting consequence of chronic inflammation, pointing out that one of the most important step in medication is to identify in time the factors initiating and maintaining inflammation.

The Role of Molecular Imaging as a Marker of Remyelination and Repair in Multiple Sclerosis

The appearance of new disease-modifying therapies in multiple sclerosis (MS) has revolutionized our ability to fight inflammatory relapses and has immensely improved patients’ quality of life. Although remarkable, this achievement has not carried over into reducing long-term disability. In MS, clinical disability progression can continue relentlessly irrespective of acute inflammation. This “silent” disease progression is the main contributor to long-term clinical disability in MS and results from chronic inflammation, neurodegeneration, and repair failure. Investigating silent disease progression and its underlying mechanisms is a challenge. Standard MRI excels in depicting acute inflammation but lacks the pathophysiological lens required for a more targeted exploration of molecular-based processes. Novel modalities that utilize nuclear magnetic resonance’s ability to display in vivo information on imaging look to bridge this gap. Displaying the CNS through a molecular prism is becoming an undeniable reality. This review will focus on “molecular imaging biomarkers” of disease progression, modalities that can harmoniously depict anatomy and pathophysiology, making them attractive candidates to become the first valid biomarkers of neuroprotection and remyelination.

Gonadal Hormone Trigger Traf6-mediated Dynamic Microglial Alterations That Correlate With Depressive Symptomatology

Backgrounds: Gonadal hormone deficiency is associated with the development of depression, but what mediates this association is unclear. To test the possibility that it reflects neuroimmune and neuroinflammatory processes, we analyzed how gonadal hormone deficiency and replacement affect microglial activation and inflammatory response during the development of depressive symptomatology in gonadectomized male mice. Methods: Adult male ICR mice received gonadectomy. Gonadal hormone levels, neuroinflammation, mciroglial activation and depressive behaviors were evaluated 7 days, 14 days, and 30 days later. Furthermore, the neuroprotective mechanism of treatment with testosterone and estradiol on depressive symptomatology were also observed.Results: Testosterone level and the ratio of testosterone to estradiol in the serum and brain tissue of mice exposed to 3-35 days of chronic unpredictable stress were much lower than in control animals. Gonadal hormone sustained deficiency in gonadectomized mice and subsequent led to acute inflammation at day 7 following castration. Activating microglia in mice exposed to 7 days of castration subsequently suppressed the proliferation of microglia, such that their numbers in hippocampus and cortex were lower than the numbers in sham-operated mice after 30 days of castration. Here, we showed that gonadal hormone deficiency induces Traf6-mediated microglia activation, a type of inflammatory mediator. Microglia treated in this way for long time showed down-regulation of activation markers, abnormal morphology and depressive-like behaviors. Restoration and maintenance of a fixed ratio of testosterone to estradiol significantly suppressed microglial activation, neuronal necroptosis, dramatically inducing hippocampal neurogenesis and reducing depressive behaviors via the suppression of Traf6/TAK1 pathway. Conclusions: These findings suggest that activated or immunoreactive microglia contribute to gonadal hormone deficiency-induced depression, as well as testosterone and estradiol exert synergistic anti-depressant effects via suppressing microglial activaton in gonadectomized male mice, possibly through Traf6 signaling.

Curcumin Nanoparticles Enhance Antioxidant Efficacy of Diclofenac Sodium in Experimental Acute Inflammation

We investigated the in vivo effect of curcumin nanoparticles (nC) in addition to diclofenac sodium on local edema and oxidative stress parameters in carrageenan-induced paw edema on rats. Seven groups were investigated: control group (C), the acute inflammation (AI) group, an AI group treated with Diclofenac (AID, 5 mg/kg b.w. Diclofenac sodium), two AI groups treated with cC (conventional Curcumin)—AIC200 and AIcC200D (D = Diclofenac, 200 represent the concentration of active substance expressed in mg/kg b.w.), and two AI groups with nC (Curcumin nanoparticles)—AIC200 and AIcC200D. Serum and tissue oxidative stress was assessed by measuring five parameters. Curcumin nanoparticles alone and in combination with D better reduced the paw edema than D alone (p < 0.027). The rats treated with D and nC (AIcC200D) had the highest inhibition percentage on edema, reaching the maximum level of inhibition (81%) after 24 h. Conventional curcumin and nC presented antioxidant effects in acute inflammation, with significantly better results obtained for nC. The pro-oxidant markers were reduced up to 0.3 by the cC and up to 0.4 times by the nC and both solutions increased the antioxidant markers up to 0.3 times. The nC enhanced the antioxidative efficacy of D, as this combination reduced the pro-oxidant markers up to 1.3 times. Curcumin nanoparticles could represent a therapeutic option in association with classical nonsteroidal anti-inflammatory medication in acute inflammation, as they might offer a reduction of drug dose and possible limitation of their associated side effects.

Acute Diffuse Peritonitis Due to Spontaneous Rupture of an Infected Endometrioma: A Case Report

Background. Endometriosis is defined as a chronic, inflammatory, estrogen-dependent gynaecologic disease. It affects approximately 5–10% of reproductive-age women worldwide. Ovarian endometriosis is the most frequent form of this condition. Endometriotic cysts are found in about 17–44% of women diagnosed with endometriosis. It is well known, that ovarian endometriomas can cause infertility and chronic pelvic pain. Enlarging cysts can also cause ovarian torsion. In addition, ovarian endometriosis slightly increases the risk for ovarian cancer. The rupture of endometriotic ovarian cysts is an exceptional complication. According to the literature, the prevalence is less than 3% among women with endometriosis. The rupture of an ovarian endometrioma can cause acute peritonitis, which can lead to sepsis, septic shock and can be lethal. The occurrence of abscesses within an ovarian endometrioma is an extremely rare complication. Generally, the origin of infected endometriotic ovarian cysts is related to the previous invasive procedures involving pelvic organs or the use of intrauterine devices. Also, ovarian abscesses can be caused by the hematogenous or lymphatic spread of bacteria. Although, the literature points out that infection of endometriotic ovarian cysts can develop spontaneously. In these rare cases, reservoir and route of infection remains an enigma.Case report. A 49-year-old female was brought to the emergency room with severe generalized lower abdominal pain (6/10) and three days lasting fever. Abdominal examination revealed diffuse abdominal pain with anterior abdominal wall muscle tension. Painful solid masses were felt on both sides of the uterus during the pelvic examination. Cystic masses were detected in both ovaries during transvaginal sonography. Computer tomography (CT) of the abdomen and pelvis revealed abnormal changes in both ovaries. A small amount of free fluid was found in the pelvic cavity along with thickened pelvic peritoneum. Suspecting acute peritonitis and bilateral tubo-ovarian abscesses, surgical treatment was performed. Lower midline laparotomy with bilateral adnexectomy and abdominal lavage with 4000 ml normal saline were done. The outcome of peritonitis was evaluated using the Mannheim peritonitis index (MPI=17 – low risk of morbidity and mortality). The histopathological examination revealed the diagnosis of bilateral endometriotic cysts complicated with acute inflammation, with associated acute inflammation of both fallopian tubes. Microbiological cultures from the purulent fluid were negative.Conclusions. Although the occurrence of abscesses within an ovarian endometrioma is an extremely rare finding in clinical practice, it has to be considered by gynaecologists because it might result in a surgical emergency that can be life-threatening. Being aware of the risk factors of abscesses within an endometrioma can lead to an early diagnosis of this rare condition and help to avoid serious complications.

CXCR4 and CXCR7 Inhibition Ameliorates the Formation of Platelet–Neutrophil Complexes and Neutrophil Extracellular Traps through Adora2b Signaling

Peritonitis and peritonitis-associated sepsis are characterized by an increased formation of platelet–neutrophil complexes (PNCs), which contribute to an excessive migration of polymorphonuclear neutrophils (PMN) into the inflamed tissue. An important neutrophilic mechanism to capture and kill invading pathogens is the formation of neutrophil extracellular traps (NETs). Formation of PNCs and NETs are essential to eliminate pathogens, but also lead to aggravated tissue damage. The chemokine receptors CXCR4 and CXCR7 on platelets and PMNs have been shown to play a pivotal role in inflammation. Thereby, CXCR4 and CXCR7 were linked with functional adenosine A2B receptor (Adora2b) signaling. We evaluated the effects of selective CXCR4 and CXCR7 inhibition on PNCs and NETs in zymosan- and fecal-induced sepsis. We determined the formation of PNCs in the blood and, in addition, their infiltration into various organs in wild-type and Adora2b−/− mice by flow cytometry and histological methods. Further, we evaluated NET formation in both mouse lines and the impact of Adora2b signaling on it. We hypothesized that the protective effects of CXCR4 and CXCR7 antagonism on PNC and NET formation are linked with Adora2b signaling. We observed an elevated CXCR4 and CXCR7 expression in circulating platelets and PMNs during acute inflammation. Specific CXCR4 and CXCR7 inhibition reduced PNC formation in the blood, respectively, in the peritoneal, lung, and liver tissue in wild-type mice, while no protective anti-inflammatory effects were observed in Adora2b−/− animals. In vitro, CXCR4 and CXCR7 antagonism dampened PNC and NET formation with human platelets and PMNs, confirming our in vivo data. In conclusion, our study reveals new protective aspects of the pharmacological modulation of CXCR4 and CXCR7 on PNC and NET formation during acute inflammation.