Engineered urolithin A-laden functional polymer-lipid hybrid nanoparticles prevent cisplatin-induced proximal tubular injury in vitro.

Functional polymer-lipid hybrid nanoparticles (H-NPs) are a promising class of nanocarriers that combine the benefits of polymer and lipid nanoparticles, offering biocompatibility, structural stability, high loading capacity, and, most importantly, superior surface functionalization. Here, we report the synthesis and design of highly functional H-NPs with specificity toward the transferrin receptor (TfR), using a small molecule ligand, gambogic acid (GA). A fluorescence study revealed the molecular orientation of H-NPs, where the lipid-dense core is surrounded by a polymer exterior, functionalized with GA. Urolithin A, an immunomodulator and anti-inflammatory agent, served as a model drug-like compound to prepare H-NPs via traditional emulsion-based techniques, where H-NPs led to smaller particles (132 nm) and superior entrapment efficiencies (70 % at 10 % drug loading) compared to GA-conjugated polymeric nanoparticles (P-NPs) (157 nm and 52 % entrapment efficiency) and solid lipid nanoparticles (L-NPs) (186 nm and 29 % entrapment efficiency). H-NPs showed superior intracellular accumulation compared to individual NPs using human small intestinal epithelial (FHs 74) cells. The in vitro efficacy was demonstrated by flow cytometry analysis, in which UA-laden H-NPs showed excellent anti-inflammatory properties in cisplatin-induced injury in healthy human proximal tubular cell (HK2) model by decreasing the TLR4, NF-κß, and IL-ß expression. This preliminary work highlights the potential of H-NPs as a novel functional polymer-lipid drug delivery system, establishing the foundation for future research on its therapeutic potential in addressing chemotherapy-induced acute kidney injury in cancer patients.

Superomedial pedicle skin-reducing mastectomy in ptotic and large-sized breasts with two-stage reconstruction through transaxillary video-assisted technique: An effective surgical and anesthetic approach.

Introduction: Skin-reducing mastectomy has been applied to several surgical techniques in which subcutaneous mastectomy is associated with various types of skin reduction, with preservation of a lower dermal flap to reinforce the inferior lateral seat of an implant. The aim of the study is to present a case series of patients with pendulous/ptotic and/or large-sized breasts treated for breast cancer at the Breast Surgery Unit of Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Naples, Italy, with the superomedial pedicle skin-reducing mastectomy technique, two-stage reconstruction, and transaxillary video-assisted technique, when a postoperative radiotherapy was indicated. We verified its effectiveness by discussing its results, especially in patients who are candidates for postmastectomy radiotherapy. Materials and methods: A single-center retrospective study was performed between January 2020 and March 2021 on a prospectively filled database of conservative mastectomies. Of the 64 patients who underwent nipple/skin-sparing mastectomies in the mentioned period, 17 (mean age 46 years, range 30-62 years) were treated with superomedial pedicle skin-reducing mastectomy, with two-stage breast reconstruction through transaxillary video-assisted replacement expander with definitive prosthesis and contralateral symmetrization, selected for postmastectomy radiotherapy. Results: We had only three minor complications. No flap necrosis, no infections, no breast seromas, and no reconstructive failures were observed. During follow-up of the patients treated with video-assisted reconstruction, there were no cases of infection, hematoma, implant rupture, or suture dehiscence in the reconstructed breast. Discussion: Skin-reducing mastectomy with superomedial pedicle is a safe and reliable procedure to treat breast cancer in selected patients, i.e., those with pendulous/ptotic and or large-sized breasts. Particularly, in patients who undergo postmastectomy radiotherapy, the two-stage reconstruction with video-assisted transaxillary endoscopic approach can find its main indication, using incisions positioned far from the mammary region, offering numerous advantages.

Columbia spotted frogs (Rana luteiventris) have characteristic skin microbiota that may be shaped by cutaneous skin peptides and the environment.

Global amphibian declines due to the fungal pathogen Batrachochytrium dendrobatidis (Bd) have led to questions about how amphibians defend themselves against skin diseases. A total of two amphibian defense mechanisms are antimicrobial peptides (AMPs), a component of amphibian innate immune defense and symbiotic skin bacteria, which can act in synergy. We characterized components of these factors in four populations of Columbia spotted frogs (Rana luteiventris) to investigate their role in disease defense. We surveyed the ability of their AMPs to inhibit Bd, skin bacterial community composition, skin metabolite profiles and presence and intensity of Bd infection. We found that AMPs from R. luteiventris inhibited Bd in bioassays, but inhibition did not correlate with Bd intensity on frogs. R. luteiventris had two prevalent and abundant core bacteria: Rhizobacter and Chryseobacterium. Rhizobacter relative abundance was negatively correlated with AMP's ability to inhibit Bd, but was not associated with Bd status itself. There was no relationship between metabolites and Bd. Bacterial communities and Bd differ by location, which suggests a strong environmental influence. R. luteiventris are dominated by consistent core bacteria, but also house transient bacteria that are site specific. Our emergent hypothesis is that host control and environmental factors shape the microbiota on R. luteiventris.

The impact of scanning data measurements on the Acuros dose calculation algorithm configuration.

BACKGROUND: Many dose calculation algorithms for radiotherapy planning need to be configured for each clinical beam using pre-defined measurements. An optimization process adjusts the physical parameters able to estimate the energy released in the medium in any geometrical condition. This work investigates the impact of measured input data quality on the configuration of the type "c" Acuros-XB dose calculation algorithm in the Eclipse (Varian Medical Systems) treatment planning system. METHODS: Different datasets were acquired with the BeamScan water phantom (PTW) to configure 6 MV beams, for both flattened (6X) and flattening filter free mode (6FFF) for a Varian TrueBeam: (i) a correct dataset measured using a Semiflex-3D ion chamber, (ii) a set in missing lateral scatter conditions (MLS), (iii) a set with incorrect effective point of measurement (EPoM), (iv) sets acquired with PinPoint-3D chamber, DiodeP, microDiamond detectors. The Acuros-XB dose calculation algorithm (version 15.6) was configured using the reference dataset, the sets measured with the different detectors, with intentional errors, and using the representative beam data (RBD) made available by the vendor. The physical parameters obtained from each optimization process (spectrum, mean radial energy, electron contamination), were analyzed and compared. Calculated data were finally compared against the input and reference measurements. RESULTS: Concerning the physical parameters, the configurations presenting the largest differences were the MLS conditions (mean radial energy) and the incorrect EPoM (electron contamination). The calculation doses relative to the input data present low accuracy, with mean differences > 2% in some conditions. The PinPoint-3D ion chamber presented lower accuracy for the 6FFF beam. Regarding the RBD, calculations compared well with the input data used for the configuration, but not with the reference data. CONCLUSION: The MLS conditions and the incorrect setting of the EPoM lead to erroneous configurations and should be avoided. The choice of an appropriate detector is important. Whenever the representative beam data is used, a careful check under more clinical geometrical conditions is advised.

Protective effect of sodium propionate in Aß1-42 -induced neurotoxicity and spinal cord trauma.

Sodium propionate (SP) is one of the main short chain fatty acids (SCFA) that can be produced naturally through host metabolic pathways. SP have been documented and include the reduction of pro-inflammatory mediators in an in vivo model of colitis. The aim of this study is to evaluate the neuroprotective effects of SP in reducing inflammatory process associated to neurological disorders. We performed both in vitro model of Alzheimer's disease, induced by oligomeric Aß1-42 stimulation, and in in vivo model of spinal cord injury (SCI) in which neuroinflammation plays a crucial role. For in vitro model, the human neuroblastoma SH-SY5Y cell line was first differentiated with retinoic acid (100 µM) for 24 h and then stimulated by oligomeric Aß1-42 (1 µg/ml) and treated with SP at 0.1- 1-10 µM concentrations for another 24 h. Instead, the in vivo model of SCI was induced by extradural compression of the spinal cord at T6-T8 levels, and animals were treated with SP (10-30-100 mg/kg o.s) 1 and 6 h after SCI. Our results demonstrated that both in in vitro neuroinflammatory model and in vivo model of SCI the treatment with SP significantly reduced NF-κB nuclear translocation and IκBα degradation, as well as decreases COX-2 and iNOS expressions evaluated by Western blot analysis. Moreover, we showed that SP treatment significantly ameliorated histopathology changes and improved motor recovery in a dose-dependent manner. In conclusion, our results demonstrated that SP possesses neuroprotective effects, suggesting it could represent a target for therapeutic intervention in neuroinflammatory disorders.

Painful bone metastasis in elderly treated with radiation therapy: Single- or multiple-fraction regimen? A multicentre retrospective observational analysis.

BACKGROUND: Bone metastases are a frequent complication of advanced oncologic disease. Pain associated to bone metastasis is a major cause of morbidity in cancer patients, especially in elderly. AIMS: The aim of this multicentric retrospective observational study is to evaluate the efficacy of different schedules of radiation therapy in elderly patients in terms of pain relief. METHODS: 206 patients over the age of 60 were enrolled in 1 year time for a multicentre retrospective observational study. Patients were treated with palliative purposes for painful bone metastases. RESULTS: Pain intensity difference (PID) was found in 72% of patients. Reported PID was statistically significant for p < 0.01. Pain intensity measured by a point numeric rating scale was statistically significant reduced for p < 0.05 by one-fraction regimen compared to other two regimens. DISCUSSION: In recent years, numerous studies have evaluated the most appropriate regimen of fractionation in individual cases, despite this, a consensus about the best schedule is still debated. CONCLUSIONS: On our analysis, single-fractionation scheme (8 Gy) confirmed to be statistical significant effective in providing pain reduction due to bone metastases. Radiation therapy provides significant pain relief of symptomatic bone metastases, but appropriate radiotherapy scheduled is needed in order to get significant response to treatment. Multidisciplinary approach is warranted to value the balance between the therapeutic objectives and the patient quality of life.

PPAR-α Modulates the Anti-Inflammatory Effect of Melatonin in the Secondary Events of Spinal Cord Injury.

Melatonin is the principal secretory product of the pineal gland, and its role as an immunomodulator is well established. Recent evidence shows that melatonin is a scavenger of oxyradicals and peroxynitrite and reduces the development of inflammation and tissue injury events associated with spinal cord trauma. Previous results suggest that peroxisome proliferator-activated receptor α (PPAR-α), a nuclear receptor protein that functions as a transcription factor activated by fatty acids, plays a role in control of secondary inflammatory process associated with spinal cord injury (SCI).With the aim to characterize the role of PPAR-α in melatonin-mediated anti-inflammatory activity, we tested the efficacy of melatonin (30 mg/kg) in an experimental model of spinal cord trauma, induced in mice, by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy, and comparing mice lacking PPAR-α (PPAR-α KO) with wild-type (WT) mice.The results obtained indicate that melatonin-mediated anti-inflammatory activity is weakened in PPAR-α KO mice, as compared to WT controls. In particular, melatonin was less effective in PPAR-α KO, compared to WT mice, as evaluated by inhibition of the degree of spinal cord inflammation and tissue injury, neutrophil infiltration, pro-inflammatory cytokine expression, nuclear factor κB (NF-κB) activation, and inducible nitric oxide synthase (iNOS) expression. This study indicates that PPAR-α can contribute to the anti-inflammatory activity of melatonin in SCI.

Risk Differences Between Prediabetes And Diabetes According To Breast Cancer Molecular Subtypes.

Hyperglycemia and hyperinsulinemia may play a role in breast carcinogenesis and prediabetes and diabetes have been associated with increased breast cancer (BC) risk. However, whether BC molecular subtypes may modify these associations is less clear. We therefore investigated these associations in all cases and by BC molecular subtypes among women living in Southern Italy. Cases were 557 patients with non-metastatic incident BC and controls were 592 outpatients enrolled during the same period as cases and in the same hospital for skin-related non-malignant conditions. Adjusted multivariate logistic regression models were built to assess the risks of developing BC in the presence of prediabetes or diabetes. The analyses were repeated by strata of BC molecular subtypes: Luminal A, Luminal B, HER2+, and Triple Negative (TN). Prediabetes and diabetes were significantly associated with higher BC incidence after controlling for known risk factors (OR = 1.94, 95% CI 1.32-2.87 and OR = 2.46, 95% CI 1.38-4.37, respectively). Similar results were seen in Luminal A and B while in the TN subtype only prediabetes was associated with BC (OR = 2.43, 95% CI 1.11-5.32). Among HER2+ patients, only diabetes was significantly associated with BC risk (OR = 3.04, 95% CI 1.24-7.47). Furthermore, when postmenopausal HER2+ was split into hormone receptor positive versus negative, the association with diabetes remained significant only in the former (OR = 5.13, 95% CI 1.53-17.22). These results suggest that prediabetes and diabetes are strongly associated with BC incidence and that these metabolic conditions may be more relevant in the presence of breast cancer molecular subtypes with positive hormone receptors. J. Cell. Physiol. 232: 1144-1150, 2017. © 2016 Wiley Periodicals, Inc.

Body weight and risk of molecular breast cancer subtypes among postmenopausal Mediterranean women.

Breast cancer (BC) is the most common malignant tumor in women, obesity is associated with increased BC incidence and mortality and high levels of circulating insulin may negatively impact on cancer incidence. In the present study, we investigated whether the strength of several anthropometric and metabolic parameters varies between BC molecular subtypes. Eligible cases were 991 non-metastatic BC patients recruited between January 2009 and December 2013. Anthropometric, clinical and immunohistochemical features were measured. Multivariate logistic regression models were built to assess HER2 positive BC risk, comparing (a) triple positive (TP) with luminal A, luminal B and triple negative (TN) and (b) HER2-enriched group with luminal A, luminal B and TN. We stratified patients in pre- and post-menopause: significant differences emerged for luminal A in relation to age: they were more likely to be older compared to other groups. Among postmenopausal patients, the adjusted multivariate analysis showed that high BMI and high waist circumference were inversely correlated to TP subtype when compared to luminal B (OR=0.48 and OR=0.49, respectively). Conversely, HOMA-IR was a risk factor for TP when compared to luminal A and TN (OR=2.47 and OR=3.15, respectively). Our findings suggest a potential role of higher abdominal fat in the development of specific BC molecular subtypes in postmenopausal women. Moreover, they support a potential role of insulin resistance in the development of HER2 positive BC, although this role appears to be stronger when hormone receptors are co-expressed, suggesting a difference in the etiology of these two BC subtypes.

A new co-micronized composite containing palmitoylethanolamide and polydatin shows superior oral efficacy compared to their association in a rat paw model of carrageenan-induced inflammation.

Palmitoylethanolamide (PEA), a special food for medical purposes, has anti-inflammatory and neuroprotective effects. Nevertheless, PEA lacks direct ability to prevent free radical formation. Polydatin (PLD), a natural precursor of resveratrol, has antioxidant activity. The combination of PEA and PLD could have beneficial effects on oxidative stress induced by inflammatory processes. In the present study, we compared the effects of micronized PEA (PEA-m) and PLD association (PEA-m+PLD) with a new co-micronized composite containing PEA and PLD (m(PEA/PLD)) in the rat paw model of carrageenan (CAR)-induced acute inflammation. Intraplantar injection of CAR led to a time-dependent development of peripheral inflammation, in terms of paw edema, cytokine release in paw exudates, nitrotyrosine formation, inducible nitric oxide synthase and cyclooxygenase-2 expression. m(PEA/PLD) reduced all measured parameters. Thermal hyperalgesia and mechanical allodynia were also markedly reduced. At the spinal cord level, manganese superoxide dismutase (MnSOD) was found to be nitrated and subsequently deactivated. Further, m(PEA/PLD) treatment increased spinal MnSOD expression, prevented IkB-α degradation and nuclear factor-κB translocation, suggesting a possible role on central sensitization. m(PEA/PLD) showed more robust anti-inflammatory and anti-hyperalgesic effects compared to the simple association of PEA-m and PLD. This composite formulation approach opens a new therapeutic strategy for the development of novel non-narcotic anti-hyperalgesic agents.

A novel protective formulation of Palmitoylethanolamide in experimental model of contrast agent induced nephropathy.

Contrast-induced nephropathy (CIN) is a complication in patients after administration of iodinated contrast media. Several risk factors contribute to the development and progression of CIN, including hypertension, diabetes, and dyslipidemia. Animal models of CIN by surgical intervention to reproduce its clinical and pathology has been developed, and thus, therapeutic methods tested. Palmitoylethanolamide (PEA) is a member of the fatty acid ethanolamine family with analgesic and anti-inflammatory effects. In this study, we analyzed streptozotocin-induced diabetes model and in an another set of experiment a surgical remotion of the kidney with the aim of evaluating effect of ultramicronized Palmitoylethanolamide (PEA-um(®)) on contrast induced renal disfunction and glomerular morphology alteration. In a first step of our study, we demonstrated that PEA-um(®) significantly reduced CIN-mediated glomerular dysfunction, modulates Na(+) and K(+) levels in plasma and decreased urine and plasma NGAL levels and α-GST urine levels. Moreover, in a second set of experiment we investigated how PEA-um(®) reduced creatinine and BUN plasma levels after nephrectomy, ameliorate renal and medullary blood flow and re-established renal parenchymal after CIN induction as well as after nephrectomy. Take together our results demonstrated that PEA-um(®) are able to preventing CIN in diabetic rats and alteration of biochemical parameters after nephrectomy.

Laparoscopic pancreatectomy: Did the indications change? A review from literature.

Pancreatic Cancer (PC) is the fourth cause of death for tumors in Western countries. Symptoms are not specific, and can vary according to the tumor size and place. Diagnostic workup includes CA 19-9, CT and MRI. Surgery is the only treatment for PC, associated to radio-chemo therapy. Laparoscopic approaches are actually used for PC treatment in few specialized centers, and could be an alternative to laparotomic surgery. The aim of our study is to evaluate the efficacy of laparoscopy for PC treatment compared to laparotomy. We reviewed 19 articles in literature to assess the feasibility and efficacy of Laparoscopic Distal Pancreatectomy (LDP) and Laparoscopic Pancreaticoduodenectomy (LPD). The results have shown that LDP is nowadays a safe technique, and the outcomes are comparable to laparotomic surgery. Regarding to LPD instead, results are controversial and the data are still not sufficient to consider this technique as a valid alternative to laparotomic surgery.

Report from the 37th san antonio breast cancer symposium, 9-13th december 2014, Texas, USA.

The 37th San Antonio Breast Cancer Symposium (SABCS) was held at the Henry B. Gonzalez Conference Centre in San Antonio, Texas, USA between the 9 and 13th of December 2014. It brought together an interaction between basic scientists and clinicians involved in the management of breast cancer. The symposium included six general sessions, poster discussion, and poster sessions. The most important highlights in the fields of advancing endocrine therapy; hormone receptor positive advanced breast cancer and hormonal resistant therapy; targeted therapies; genetics and genomics; supportive (adjunct) care; chemotherapy treatments; breast screening and risk stratification; male breast cancer and future potential directions were included here.

Intraoperative radiotherapy in early breast cancer.

BACKGROUND: Intraoperative radiotherapy (IORT) constitutes a paradigm shift from the conventional 3-5 weeks of whole-breast external beam radiotherapy (EBRT). IORT enables delivery of radiation at the time of excision of the breast tumour, targeting the area at highest risk of recurrence, while minimizing excessive radiation exposure to healthy breast tissue. The rationale for IORT is based on the observation that over 90 per cent of local recurrences after breast-conserving surgery occur at or near the original operation site. METHODS: This article reviews trials of IORT delivered with different techniques and devices. RESULTS: IORT is a very attractive option for delivering radiotherapy, reducing the traditional fractionated treatment to a single fraction administered at the time of surgery. IORT has been shown to be associated with reduced toxicity and has several potential benefits over EBRT. Only two randomized clinical trials have been published to date. The TARGIT-A and ELIOT trials have demonstrated that IORT is associated with a low rate of local recurrence, although higher than that after EBRT (TARGIT-A: 3·3 versus 1·3 per cent respectively, P = 0·042; ELIOT: 4·4 versus 0·4 per cent, P < 0·001). However, the local recurrence rate for IORT fell within the predefined 2·5 per cent non-inferiority margin in TARGIT-A, and the 7·5 per cent equivalence margin in ELIOT. CONCLUSION: Longer follow-up data from existing trials, optimization of patient criteria and cost-effectiveness analyses are needed. Based on the current evidence, IORT can be offered as an alternative to EBRT to selected patients within agreed protocols, and outcomes should be monitored within national registries.

Rare mendelian primary immunodeficiency diseases associated with impaired NF-κB signaling.

Mendelian primary immunodeficiency diseases (MPIDs) are rare disorders affecting distinct constituents of the innate and adaptive immune system. Although they are genetically heterogeneous, a substantial group of MPIDs is due to mutations in genes affecting the nuclear factor-κB (NF-κB) transcription pathway, essential for cell proliferation and cell survival and involved in innate immunity and inflammation. Many of these genes encode for crucial regulatory components of the NF-κB pathway and their mutations are associated with immunological and developmental signs somehow overlapping in patients with MPIDs. At present, nine different MPIDs listed in the online mendelian inheritance in man (OMIM) are caused by mutations in at least nine different genes strictly involved in the NF-κB pathway that result in defects in immune responses. Here we report on the distinct function of each causative gene, on the impaired NF-κB step and more in general on the molecular mechanisms underlining the pathogenesis of the disease. Overall, the MPIDs affecting the NF-κB signalosome require a careful integrated diagnosis and appropriate genetic tests to be molecularly identified. Their discovery at an ever-increasing rate will help establish a common therapeutic strategy for a subclass of immunodeficient patients.

The first case of acinic cell carcinoma of the breast within a fibroadenoma: case report.

A case of acinic cell carcinoma of the breast is reported in a 26-year-old woman. She presented a lump in her right breast, that seemed to be a fibroadenoma. The open biopsy revealed a well-bordered fibroadenoma, together with a proliferation of cells characterized by serous acinar differentiation and eosinophilic cytoplasmic granules. Tumor cells stained for amylase, lysozyme, α-1-antichymotripsin, epithelial membrane antigen, S-100 protein, pan-cytokeratin, cytokeratin 7 and E-cadherin. Estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 overexpression, CD10, P63, smooth muscle actin, cytokeratin 5/6 were negative. The sentinel node was negative. 8 months after surgery she is in good clinical conditions without recurrence or metastases.

Acinic cell carcinoma of the breast: review of the literature.

INTRODUCTION: The breast and salivary gland tissue share embryologic and thus pathological similarities. Acinic cell carcinoma (ACC) is a typical tumor in salivary glands, but rarely arises in breast too. We reviewed 38 cases of mammary ACC reported in literature and our case, the first ACC born within a fibroadenoma. MATERIALS AND METHODS: Data were collected by a research for the key words acinic cell carcinoma breast on Pubmed in March 2014, including a case treated in our department. All reviewed cases were compared for clinical approach and histological pattern. RESULTS: To date 23 articles presenting cases of ACC of the breast are reported in literature. We included in our review 38 cases previously described and one new case. The histological pattern was predominantly solid with a microglandular structure. All the tumor cells were cytologically characterized by monotonous round cells with a finely granular, weakly eosinophilic, or clearly vacuolated cytoplasm. The most of the cells were intensely stained with anti-lysozime, anti-amylase, anti-α1-chimotripsin, anti-EMA and anti-S100 protein antisera. Immunohistochemistry was also performed to point out: estrogen receptor (ER), progesterone receptor (PR), androgen receptors (AR), human epidermal growth factor receptor 2 overexpression (HER2/neu), E-cadherin (E-cad), cytokeratin-7 (CK7), gross cystic disease fluid protein 15 (GCDFP15), smooth muscle actin (SMA). CONCLUSION: ACC of the breast is a rare tumor, showing similarities with the salivary gland counterpart, above all in terms of good prognosis, and differences from the ordinary invasive breast carcinoma. Further investigations are needed to elucidate the true histogenesis and the correct treatment.

Madelung disease : report of a case and review of the literature.

Madelung disease is a rare disorder characterized by the presence of multiple, symmetric, nonencapsulated fatty accumulations diffusely involving the cheeks, the neck, the upper trunk, the shoulder girdle area, and the upper extremities. The cause of this syndrome is unknown, but it has been associated with alcoholism in 60% to 90% of -patients. The long-term lipomatous deposits are often large and cosmetically deforming, and the upper aerodigestive tract and great veins may be compressed. We report the case of a man with MD, involving the cervical and upper dorsal -regions, who underwent surgical treatment at our Department.

NADPH-oxidase 2 activation promotes opioid-induced antinociceptive tolerance in mice.

The analgesic effectiveness of long-term opioid therapies is compromised by the development of antinociceptive tolerance linked to the overt production of peroxynitrite (ONOO(-), PN), the product of the interaction between superoxide (O2(-), SO) and nitric oxide (NO), and to neuroinflammatory processes. We have recently reported that in addition to post-translational nitration and inactivation of mitochondrial manganese superoxide dismutase (MnSOD), activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase holoenzyme (NOX) in the spinal cord is a major source for the overt production of superoxide-derived PN during the development of morphine-induced antinociceptive tolerance. However, the NOX complex involved in these processes is not known. The objective of these studies is to identify a potential role for the NOX2 complex, an enzyme involved in inflammation. Mice lacking the catalytic subunit of NOX2 (Nox2(-/-)) or its regulatory subunit, p47(phox) (p47(phox)(-/-)), developed antinociceptive tolerance similar to wildtype (wt) mice after 3 days of continuous morphine. However, while wt mice continue to develop tolerance by day six, morphine analgesia was restored in both Nox2(-/-) and p47(phox)(-/-) mice. Moreover, the loss of Nox2 or p47 did not affect acute morphine analgesia in naïve mice. In wt mice, antinociceptive tolerance was associated with increased activation of NOX, nitration of MnSOD, and proinflammatory cytokines production in the spinal cord. These events were markedly attenuated in Nox2(-/-) and p47(phox)(-/-) mice and instead, there was enhanced formation of antiinflammatory cytokine (IL4 and IL10) production. These results suggest that NOX2 activity provides a significant source of superoxide-derived PN to undertake post-translational modifications of mitochondrial MnSOD and to engage neuroinflammatory signaling in the spinal cord associated with opioid-induced antinociceptive tolerance. Thus, NOX2 may provide a potential target for adjuvant therapy to protect opioid analgesia.