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Background/Aim: Although the reciprocal translocation t(9;22)(q34;q11) is a hallmark of chronic myeloid leukemia (CML), it is also present in acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Depending on the gene's breakpoint, it is possible to obtain three isoforms, among which p190 stands out for the poor prognosis it induces whenever it appears. Due to the genomic instability induced by BCR::ABL1, it is proposed to expand the applicability of poly-ADP-ribose polymerase-1 (PARP1) and its inhibitors in hematological neoplasms. Materials and Methods: We measured the expression levels of PARP1 by quantitative real-time PCR (qPCR) using TaqMan®, correlating its expression with BCR::ABL1 p190+, to evaluate its influence in the clinic of adult patients. Results: We found that PARP1 is expressed differently in ALL, AML and CML and that p190 transcripts do not follow a linear pattern in these populations. We also found that PARP1 expression is not correlated with age, white blood cell and the amount of p190 transcripts. Conclusion: Despite the lack of statistical correlation between the variables analyzed, the role of PARP1 in BCR::ABL1 leukemia cannot be ruled out, given the instability profile promoted by this translocation. Finally, further studies involving a larger sample of patients are needed, as well as investigations into other molecular pathways that may impact on the pathogenesis of different BCR::ABL1 leukemic subtypes. [ABSTRACT FROM AUTHOR]

Background: Pain management is a major unmet need in people with rheumatoid arthritis (RA). Although many patients are treated with disease modifying anti-rheumatic drugs (DMARDS), including biologic therapies, many people with RA continue to experience significant pain. We aimed to determine whether performing a comprehensive pain evaluation is feasible in people with active RA receiving conventional DMARDs and biologic therapies. Methods: The BIORA-PAIN feasibility study was an open-label, randomised trial, which recruited participants suitable for treatment with biologic therapy. The primary feasibility outcomes were recruitment, randomisation and retention of eligible participants. All participants underwent pain assessment for nociceptive, neuropathic and nociplastic pain during the 12-month study period, with quarterly assessments for VAS (Visual Analogue Scale) pain, painDETECT and QST (quantitative sensory testing). This trial was registered in clinicaltrials.gov NCT04255134. Results: During the study period, 93 participants were screened of whom 25 were eligible: 13 were randomised to adalimumab and 12 to abatacept. Participant recruitment was lower than expected due to the COVID-19 pandemic. Pain assessments were practical in the clinical trial setting. An improvement was observed for VAS pain from baseline over 12 months, with a mean (SEM) of 3.7 (0.82) in the abatacept group and 2.3 (1.1) in the adalimumab group. There was a reduction in painDETECT and improvement in QST measures in both treatment groups during the study. Participant feedback included that some of the questionnaire-based pain assessments were lengthy and overlapped in their content. Adverse events were similar in both groups. There was one death due to COVID-19. Conclusions: This first-ever feasibility study of a randomised controlled trial assessing distinct modalities of pain in RA met its progression criteria. This study demonstrates that it is feasible to recruit and assess participants with active RA for specific modalities of pain, including nociceptive, neuropathic and nociplastic elements. Our data suggests that it is possible to stratify people for RA based on pain features. The differences in pain outcomes between abatacept and adalimumab treated groups warrant further investigation. Trial registration: NCT04255134, Registered on Feb 5, 2020. [ABSTRACT FROM AUTHOR]

The mechanisms of the chronic pain and depression comorbidity have gained significant attention in recent years. The complement system, widely involved in central nervous system diseases and mediating non-specific immune mechanisms in the body, remains incompletely understood in its involvement in the comorbidity mechanisms of chronic pain and depression. This review aims to consolidate the findings from recent studies on the complement system in chronic pain and depression, proposing that it may serve as a promising shared therapeutic target for both conditions. Complement proteins C1q, C3, C5, as well as their cleavage products C3a and C5a, along with the associated receptors C3aR, CR3, and C5aR, are believed to have significant implications in the comorbid mechanism. The primary potential mechanisms encompass the involvement of the complement cascade C1q/C3- CR3 in the activation of microglia and synaptic pruning in the amygdala and hippocampus, the role of complement cascade C3/C3a-C3aR in the interaction between astrocytes and microglia, leading to synaptic pruning, and the C3a-C3aR axis and C5a-C5aR axis to trigger inflammation within the central nervous system. We focus on studies on the role of the complement system in the comorbid mechanisms of chronic pain and depression. [ABSTRACT FROM AUTHOR]

Background and Aim: Osteoarthritis (OA) stands as the prevailing degenerative joint condition, and although it is widely observed, its precise causes are not fully understood. The main focus of the study was to assess the role of Complement C3 and Cathepsin D in the development of knee osteoarthritis (OA), which is the most prevalent degenerative joint disease. Materials and Methods: The study was carried out in 20 patients with knee OA and 20 healthy control group. OA knee (Grade II/III, Radiological Kellgren and Lawrence (K/L) classification), aged between 40 and 65 years were able to walk with a painful knee. The study also included healthy age-matched controls. The concentration of Complement C3 and Cathepsin D in serum was determined. Results: The results of the present study demonstrated significantly (P < 0.001) higher concentrations of C3 and Cathepsin D in OA patients in comparison to that of the healthy aged matched control group. Conclusions: The analysis showed that inflammatory markers, Complement C3 as well as Cathepsin D may be used as diagnostic markers of knee OA. The observations suggest that the activation of the complement system mainly affects processes within the joints, while C3 appears to play a central role in generating a systemic inflammatory response. [ABSTRACT FROM AUTHOR]

The nervous and immune systems are the primary sensory interfaces of the body, allowing it to recognize, process, and respond to various stimuli from both the external and internal environment. These systems work in concert through various mechanisms of neuro-immune crosstalk to detect threats, provide defense against pathogens, and maintain or restore homeostasis, but can also contribute to the development of diseases. Among peripheral sensory neurons (PSNs), nociceptive PSNs are of particular interest. They possess a remarkable capability to detect noxious stimuli in the periphery and transmit this information to the brain, resulting in the perception of pain and the activation of adaptive responses. Pain is an early symptom of cancer, often leading to its diagnosis, but it is also a major source of distress for patients as the disease progresses. In this review, we aim to provide an overview of the mechanisms within tumors that are likely to induce cancer pain, exploring a range of factors from etiological elements to cellular and molecular mediators. In addition to transmitting sensory information to the central nervous system, PSNs are also capable, when activated, to produce and release neuropeptides (e.g., CGRP and SP) from their peripheral terminals. These neuropeptides have been shown to modulate immunity in cases of inflammation, infection, and cancer. PSNs, often found within solid tumors, are likely to play a significant role in the tumor microenvironment, potentially influencing both tumor growth and anti-tumor immune responses. In this review, we discuss the current state of knowledge about the degree of sensory innervation in tumors. We also seek to understand whether and how PSNs may influence the tumor growth and associated antitumor immunity in different mouse models of cancer. Finally, we discuss the extent to which the tumor is able to influence the development and functions of the PSNs that innervate it. [ABSTRACT FROM AUTHOR]

Disc degeneration and vertebral endplate bone marrow lesions called Modic changes are prevalent spinal pathologies found in chronic low back pain patients. Their pathomechanisms are complex and not fully understood. Recent studies have revealed that complement system proteins and interactors are dysregulated in disc degeneration and Modic changes. The complement system is part of the innate immune system and plays a critical role in tissue homeostasis. However, its dysregulation has also been associated with various pathological conditions such as rheumatoid arthritis and osteoarthritis. Here, we review the evidence for the involvement of the complement system in intervertebral disc degeneration and Modic changes. We found that only a handful of studies reported on complement factors in Modic changes and disc degeneration. Therefore, the level of evidence for the involvement of the complement system is currently low. Nevertheless, the complement system is tightly intertwined with processes known to occur during disc degeneration and Modic changes, such as increased cell death, autoantibody production, bacterial defense processes, neutrophil activation, and osteoclast formation, indicating a contribution of the complement system to these spinal pathologies. Based on these mechanisms, we propose a model how the complement system could contribute to the vicious cycle of tissue damage and chronic inflammation in disc degeneration and Modic changes. With this review, we aim to highlight a currently understudied but potentially important inflammatory pathomechanism of disc degeneration and Modic changes that may be a novel therapeutic target. [ABSTRACT FROM AUTHOR]

The complement system comprises intrinsic complement components, complement regulatory pro⁃ teins, and complement receptors. Complement activation plays a role in promoting the sensitization of peripheral pain re⁃ ceptors, enhancing immune cell activity, and participating in the regulation of axon regeneration after nerve injury. The interaction of the complement system contributes to the development and maintenance of pathological pain, affecting the dorsal root ganglion neurons, spinal dorsal horn, and brain. Consequently, targeting the complement system holds promise as a therapeutic approach for neuropathic pain treatment. This paper reviews the progress in understanding the functions of the complement system and its implications in pathological pain, offering valuable insights for the future development of targeted drug therapies. [ABSTRACT FROM AUTHOR]

Nonsteroidal anti-inflammatory drugs (NSAIDs) are an important class of anti-inflammatory drugs widely used for the treatment of musculoskeletal disorders, mild-to-moderate pain, and fever. This review aimed to explain the functional role and possible mechanisms of the antifungal effects of NSAIDs alone or in combination with antifungal drugs in vitro and in vivo. Several studies reported that NSAIDs such as aspirin, ibuprofen, diclofenac, indomethacin, ketorolac, celecoxib, flurbiprofen, and nimesulide had antifungal activities in vitro, either fungistatic or fungicidal, against different strains of Candida, Aspergillus, Cryptococcus, Microsporum, and Trichophyton species. These drugs inhibited biofilm adhesion and development, and yeast-to-hypha conversion which may be related to a prostaglandin E2 (PGE2)/PGEx-dependent mechanism. Modulating PGE2 levels by NSAIDs during fungal infection can be introduced as a possible mechanism to overcome. In addition, some important mechanisms of the antifungal activities of NSAIDs and their new derivatives on fungi and host immune responses are summarized. Overall, we believe that using NSAIDs along with classical antifungal drugs has the potential to be investigated as a novel therapeutic strategy in clinical studies. Furthermore, combination therapy can help manage resistant strains, increase the efficacy of antifungal drugs, and reduce toxicity. [ABSTRACT FROM AUTHOR]

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusionassociated death, occurring during or within 6 hours after transfusion. Reports indicate that TRALI can be categorized as having or lacking acute respiratory distress syndrome (ARDS) risk factors. There are two types of TRALI in terms of its pathogenesis: antibody-mediated and non-antibody-mediated. The key initiation steps involve the priming and activation of neutrophils, with neutrophil extracellular traps (NETs) being established as effector molecules formed by activated neutrophils in response to various stimuli. These NETs contribute to the production and release of reactive oxygen species (ROS) and participate in the destruction of pulmonary vascular endothelial cells. The significant role of NETs in TRALI is well recognized, offering a potential pathway for TRALI treatment. Moreover, platelets, macrophages, endothelial cells, and complements have been identified as promoters of NET formation. Concurrently, studies have demonstrated that the storage of platelets and concentrated red blood cells (RBC) can induce TRALI through bioactive lipids. In this article, recent clinical and pre-clinical studies on the pathophysiology and pathogenesis of TRALI are reviewed to further illuminate the mechanism through which NETs induce TRALI. This review aims to propose new therapeutic strategies for TRALI, with the hope of effectively improving its poor prognosis. [ABSTRACT FROM AUTHOR]

Bacterial infections are often accompanied by fever and generalized muscle pain. However, the treatment of pain with an infectious aetiology has been overlooked. Thus, we investigated the impact of cannabidiol (CBD) in bacterial lipopolysaccharide (LPS)‐induced nociception. Male Swiss mice received intrathecal (i.t.) LPS injection, and the nociceptive threshold was measured by the von Frey filaments test. Spinal involvement of the cannabinoid CB2 receptor, toll‐like receptor 4 (TLR4), microglia and astrocytes were evaluated by i.t. administration of their respectively antagonists or inhibitors. Western blot, immunofluorescence, ELISA and liquid chromatography‐mass spectrometry were used to assess Cannabinoid CB2 receptors and TLR4 spinal expression, proinflammatory cytokines and endocannabinoid levels. CBD was administered intraperitoneally at 10 mg/kg. The pharmacological assay demonstrated TLR4 participation in LPS‐induced nociception. In addition, spinal TLR4 expression and proinflammatory cytokine levels were increased in this process. CBD treatment prevented LPS‐induced nociception and TLR4 expression. AM630 reversed antinociception and reduced CBD‐induced endocannabinoids up‐regulation. Increased spinal expression of the cannabinoid CB2 receptor was also found in animals receiving LPS, which was accompanied by reduced TLR4 expression in CBD‐treated mice. Taken together, our findings indicated that CBD is a potential treatment strategy to control LPS‐induced pain by attenuating TLR4 activation via the endocannabinoid system. [ABSTRACT FROM AUTHOR]

Endometriosis (EM) is a gynecological disorder that presents significant immune dysregulation in its pathophysiology. Recent studies indicate that the Complement System may play a significant role in the immune processes involved in peritoneal clearance and inflammation in EM patients. C5a is a potent anaphylatoxin molecule of complement associated with the development of inflammatory disorders, however its possible impact on EM development requires further investigation. The aim of this study was to determine the concentration of serum C5a in women with EM and to investigate its possible association with severity, symptoms, age and the timing of infertility. Ninety-four patients with EM (from stage I to IV) and 50 healthy controls were assessed for C5a serum levels. Clinical and demographic data were included in the analysis. C5a serum levels were higher in patients with EM than in controls (39.5 ng/mL vs. 26.0 ng/mL; p <.0001), but not different between the EM stages. No association was observed between C5a serum concentration and the presence of symptoms, age, symptom time or infertility time. The C5a serum levels were higher in patients with EM than in controls but not associated with the severity or clinical findings. [ABSTRACT FROM AUTHOR]

Copyright of International Journal of Cosmetic Science is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Canadian Journal of Pain is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

BACKGROUND: Oleogels represent one of the most important carriers for the delivery of lipophilic nutraceuticals. Phytosterols (PS), plant‐derived natural sterol compounds, are preferred for oleogel preparation due to their self‐assembly properties and health function. However, the relationship between the physical properties of PS‐based oleogels and the chemical stability of loaded bioactive compounds is still unclear. RESULTS: The influence of lecithin (LC) and glycerol monostearate (GMS) on the physical properties of PS‐based oleogels made of liquid coconut oil and the stability of curcumin as a model bioactive loaded in the oleogels was investigated. Results showed that the flow consistency index was much higher for GMS‐containing oleogels than that for LC‐containing oleogels. The optical microscopy and X‐ray scattering analysis showed that the addition of GMS in the PS oleogels promoted the formation of a crystal mixture with different crystal polymorph structures, whereas LC addition promoted the formation of needle‐like crystals of PS. Using curcumin as a model lipophilic nutraceutical, the GMS‐enriched PS oleogels with high crystallinity and flow consistency index exhibited a good retention ratio and scavenging activity of the loaded curcumin when stored at room temperature. CONCLUSION: This study shows that enhancing the firmness of oleogels made from PS and liquid coconut oil is beneficial to the retention and chemical stability of a loaded bioactive (curcumin). The findings of the study will boost the development of PS‐based oleogel formulations for lipophilic nutraceutical delivery. © 2022 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neuropathy (CIPN) is the most common neurologic complication of chemotherapy, resulting in symptoms like pain, sensory loss, and numbness in the hands and feet that cause lots of uneasiness in patients with cancer. They often suffer from pain so severe that it interrupts the treatment, thus invalidating the entire chemotherapy-based healing process, and significantly reducing their quality of life. In this paper, we underline the role of the complement system in CIPN, highlighting the relevance of the C5a fragment and its receptor C5aR1, whose activation is thought to be involved in triggering a cascade of events that can lead to CIPN onset. Recent experimental data showed the ability of docetaxel and paclitaxel to specifically bind and activate C5aR1, thus shining light on one of the molecular mechanisms by which taxanes may activate a cascade of events leading to neuropathy. According to these new evidence, it was possible to suggest new mechanisms underlying the pathophysiology of CIPN. Hence, the C5a/C5aR1 axis may represent a new target for CIPN treatment, and the use of C5aR1 inhibitors can be proposed as a potential new therapeutic option to manage this high unmet medical need. [ABSTRACT FROM AUTHOR]

Many invasive micro-organisms produce ‘quorum sensor’ molecules which regulate colony expansion and may modulate host immune responses. We have examined the ability of Pseudomonas Quorum Sensor (PQS) to influence cytokine expression under conditions of inflammatory stress. The administration of PQS in vivo to mice with collagen-induced arthritis (CIA) increased the severity of disease. Blood and inflamed paws from treated mice had fewer regulatory T cells (Tregs) but normal numbers of Th17 cells. However, PQS (1μM) treatment of antigen-stimulated lymph node cells from collagen-immunised mice in vitro inhibited the differentiation of CD4+IFNγ+ cells, with less effect on CD4+IL-17+ cells and no change in CD4+FoxP3+Tregs. PQS also inhibited T cell activation by anti-CD3/anti-CD28 antibodies. PQS reduced murine macrophage polarisation and inhibited expression of IL1B and IL6 genes in murine macrophages and human THP-1 cells. In human monocyte-derived macrophages, IDO1 gene, protein and enzyme activity were all inhibited by exposure to PQS. TNF gene expression was inhibited in THP-1 cells but not murine macrophages, while LPS-induced TNF protein release was increased by high PQS concentrations. PQS is known to have iron scavenging activity and its suppression of cytokine release was abrogated by iron supplementation. Unexpectedly, PQS decreased the expression of indoleamine-2, 3-dioxygenase genes (IDO1 and IDO2), IDO1 protein expression and enzyme activity in mouse and human macrophages. This is consistent with evidence that IDO1 inhibition or deletion exacerbates arthritis, while kynurenine reduces its severity. It is suggested that the inhibition of IDO1 and cytokine expression may contribute to the quorum sensor and invasive actions of PQS. [ABSTRACT FROM AUTHOR]

In this work, a biologically active curcumin molecule is used as an antibacterial agent, and the insertion of this naturally occurring biomolecule into the backbone of water-dispersible polyurethane has been successfully achieved to synthesize bio-based antibacterial textile finishes. These curcumin-based water-dispersible polyurethane (CUR-WDPU) dispersions were prepared by utilizing isophorone diisocyanate (IPDI), polyethylene glycol (PEG), dimethylolpropionic acid (DMPA) and triethylamine (TEA) following the prepolymer mixing process by incorporating variable molar quantities of curcumin (CUR). Structure elucidation of synthesized CUR-WDPU dispersions was obtained through Fourier transformed infrared spectroscopy (FTIR) which confirmed the insertion of CUR into the WDPU backbone. Using the pad-dry-cure procedure, the varying varieties of plain weave polyester/cotton blended dyed and printed textile samples were treated with synthesized CUR-WDPU finishes. The antibacterial activities of these treated textiles have been assessed, and the outcomes revealed that the insertion of curcumin into the PU polymer chain has significantly boosted the antibacterial activities of PU dispersions. These newly prepared CUR-WDPUs dispersions are proved to be eco-friendly antimicrobial finishes because these are containing natural bioactive agents such as curcumin, showing potential antibacterial applications on polyester/cotton textiles. Predominantly, this research work is an attempt toward the greener approach of novel bio-based finishing materials preferably useful for textile diligences. Future investigations of these finishes will explore the other textile assets of poly-cotton textiles without adversely influencing their color fastness and mechanical properties. [ABSTRACT FROM AUTHOR]

Purpose: The mechanisms underlying chronic postsurgical pain after joint replacement (JR) are complex, and it has been suggested that chronic postsurgical pain can develop as a result of inadequate acute pain management. Few studies have addressed acute pain after JR using specific animal models. This study aimed to develop a novel JR model focused on postsurgical pain assessment and the time course of pain recovery. Materials and Methods: Rats were allocated to the following three groups: sham (joint exposure), joint destruction (JD; resection of the femoral head), and JR (femoral head replacement using an originally developed implant). The time course of postsurgical pain behavior was measured using a dynamic weight-bearing apparatus, along with radiological assessments. The expression of calcitonin gene-related peptide-immunoreactive (CGRP-IR) neurons in the dorsal root ganglion (DRG) was evaluated by immunohistochemistry on days 28 and 42. Results: The ratio of weight-bearing distribution in the JR group gradually recovered from day 14 and reached the same level as that in the sham group on day 42, which was significantly greater than that in the JD group after day 7 (p< 0.05). Radiologically, no significant issues were found, except for transient central migration of the implant in the JR group. The percentage of CGRP-IR DRG neurons in the JR group was significantly lower than that in the JD group on day 28 (mean, 37.4 vs 58.1%, p< 0.05) and day 42 (mean, 32.3 vs 50.0%, p< 0.05). Conclusion: Our novel JR model presented acute postsurgical pain behavior that was successfully recovered to the baseline level at day 42 after surgery. Difference of the pain manifestation between the JR and JD groups could be supported by the expression of CGRP-IR in DRG neurons. This model is the first step toward understanding detailed mechanisms of post-JR pain. [ABSTRACT FROM AUTHOR]

Autoimmune murine disease models are vital tools for identifying novel targets and finding better treatments for human diseases. Complete Freund's adjuvant is commonly used to induce disease in autoimmune models, and the quality of the adjuvant/autoantigen emulsion is of critical importance in determining reproducibility. We have established an emulsification method using a standard homogenizer and specially designed receptacle. Emulsions are easy to prepare, form stable and uniform water-in-oil particles, are faster to make than the traditional syringe method, use less material and are designed to fill syringes with ease. In the present study, we have validated the emulsions for induction of experimental autoimmune encephalitis, collagen II induced arthritis, antigen induced arthritis, and delayed type hypersensitivity models. These models were induced consistently and reproducibly and, in some cases, the new method outperformed the traditional method. The method described herein is simple, cost-effective and will reduce variability, thereby requiring fewer animals for in vivo research involving animal models of autoimmune disease and in vaccine development. [ABSTRACT FROM AUTHOR]

Background: The paucity of objective and reliable measurements of pain-like behaviors has impeded the translatability of mouse models of postsurgical pain. The advanced dynamic weight-bearing (DWB) system enables evaluation of spontaneous pain-like behaviors in pain models. This study investigated the suitability and efficiency of the DWB system for assessing spontaneous pain-like behaviors and analgesic therapies in murine models of postsurgical pain. Methods: Male adult C57BL/6JJcl mice were subjected to multiple surgical pain models with distinct levels of invasiveness, including a superficial incisional pain model involving only hind paw skin incision, deep incisional pain model that also involved incision and elevation of the underlying hind paw muscles, and orthopedic pain model involving tibial bone fracture and fixation with a pin (fracture and pinning [F/P] model). Spontaneous pain-like behaviors post-surgery were evaluated using weight distribution, pawprint area of the operated paw in the DWB system, and guarding pain score. Mechanical hypersensitivity was assessed using the von Frey test. The therapeutic effects of analgesics (diclofenac and buprenorphine for the deep incision model and diclofenac for the F/P model) were evaluated using the DWB system and von Frey test. Results: The von Frey test demonstrated contradictory results between superficial and deep incisional pain models. The DWB system captured weight distribution changes in the operated hind paw, in accordance with the invasiveness and time course of wound healing in these surgical pain models. The reduction in weight-bearing on the operated paw correlated with guarding score, degree of paw swelling, and local expression of inflammatory mediators. DWB enabled accurate evaluation of the pharmacological effects of analgesics for detecting attenuation of surgery-induced weight-bearing changes in these models. Conclusion: The DWB system serves as an objective and reliable method for quantifying pain-like behaviors and evaluating the therapeutic effects of analgesics in mouse models of postsurgical pain models. [ABSTRACT FROM AUTHOR]

Types of pain in NMOSD patients including painful tonic muscle spasms, neuropathic pain, and sometimes pain due to excess loading and pain as a side effect of immunotherapy and in the context of comorbidities. Also, 46% of NMOSD patients in the current study experienced ongoing pain, and further binary logistic regression analysis showed that pain was positively correlated with the C5a level, with gender and EDSS score were identified as independent factors. Keywords: neuromyelitis optica spectrum disorders; remission; pain; C5a EN neuromyelitis optica spectrum disorders remission pain C5a 1039 1046 8 06/09/22 20220501 NES 220501 Introduction Neuromyelitis optica spectrum disorders (NMOSD) is a rare autoimmune inflammatory demyelinating disease of the central nervous system (CNS) characterized by recurrent inflammation of the optic nerve, spinal cord, and specific brain areas.[1] Compared to multiple sclerosis (MS) that primarily targets myelin, NMOSD induces irreparable neuronal cell death which leads to more severe disability and a poorer prognosis.[2] The clinical presentation of NMOSD includes severe episodes of optic neuritis that may lead to loss of vision, transverse myelitis causing paraplegia or paralysis, and sometimes brainstem encephalitis causing intractable vomiting or hiccups. Pain, which is highly prevalent in patients with NMOSD, can greatly impair quality of life.[18] In the present study, 46% of the patients with NMOSD during remission complained of current pain. [Extracted from the article]

Mesenchymal stem cells (MSCs), which are isolated from adipose tissue (AD-MSCs), umbilical cord (UC-MSCs), or bone marrow, have therapeutic potential including anti-inflammatory and immunomodulatory activities. It was recently reported that MSCs are also effective as a therapeutic treatment for neuropathic pain, although the underlying mechanisms have yet to be resolved. Therefore, in this study, we investigated the effects of human AD- and UC-MSCs on neuropathic pain and its mechanisms using rat models of partial sciatic nerve ligation (PSNL). AD- or UC-MSCs were intravenously administered 4 days after PSNL. Antinociceptive effects were then evaluated using the von Frey and weight-bearing tests. We found that, 3–9 days after the administration of AD- or UC-MSCs to PSNL-exposed rats, both the mechanical threshold and differences in weight-bearing of the right and left hind paws were significantly improved. To reveal the potential underlying antinociceptive mechanisms of MSCs, the levels of activation transcription factor 3- and ionized calcium-binding adapter molecule 1-positive cells were measured by immunohistochemical analysis. AD- and UC-MSCs significantly decreased the levels of these proteins that were induced by PSNL in the dorsal root ganglia. Additionally, UC-MSC significantly improved the PSNL-induced decrease in the myelin basic protein level in the sciatic nerve, indicating that UC-MSC reversed demyelination of the sciatic nerve produced by PSNL. These data suggest that AD- and UC-MSCs may help in the recovery of neuropathic pain via the different regulation; AD-MSCs exhibited their effects via suppressed neuronal damage and anti-inflammatory actions, while UC-MSCs exhibited their effects via suppressed neuronal damage, anti-inflammatory actions and remyelination. [ABSTRACT FROM AUTHOR]

Resveratrol has proven as potential natural antioxidant, non-flavonoid polyphenolic compound, but it has limitations such as low water solubility, which substantially restricts oral bioavailability. To enhance oral bioavailability and antioxidant potential of resveratrol by fabricating the resveratrol encapsulated oral eudragit® E100 based polymeric nano-delivery system. Resveratrol-encapsulated polymeric nanoparticles were developed by solvent extraction and diffusion method. Copolymer, eudragit® E100 polymeric matrices were used to prepared polymeric nanoparticles and in vitro physicochemically characterized. Furthermore, in vivo pharmacokinetic and antioxidant potential of optimized resveratrol-encapsulated polymeric nanoparticles was evaluated. The resveratrol-encapsulated polymeric nanoparticles exhibited optimum mean particle size (410±9.78 nm), polydispersity index (0.203±0.079) and encapsulation efficiency (66.88±5.45 %), respectively. In vitro release profile of resveratrol showed >25 % release in first 2 h in phosphate-buffered saline pH 7.4 followed by >75 % at the end of 48 h. The optimized resveratrolencapsulated polymeric nanoparticles were stable at the accelerated condition and room temperature, respectively. The optimized resveratrol-encapsulated polymeric nanoparticles demonstrated significantly higher oral bioavailability (~4.07-fold; p<0.05) as compared to pure resveratrol. Furthermore, the optimized resveratrol-encapsulated polymeric nanoparticles were evaluated for free radical scavenging activity and showed to increase the activity with time i.e. after 72 h, it was the same as pure resveratrol but at 24 h no increase in antioxidant activity was observed with optimized resveratrol-encapsulated polymeric nanoparticles. Furthermore, half-maximal inhibitory concentration of the optimized resveratrol-encapsulated polymeric nanoparticles was decreased with time. Results are suggesting that resveratrol-encapsulated polymeric nanoparticles are the promising approach using eudragit® E100 as a polymeric material to enhance oral bioavailability and antioxidant potential of insoluble resveratrol. [ABSTRACT FROM AUTHOR]

Fungal infections are responsible for high mortality rates in immunocompromised and high‐risk surgical patients. Therapy failures during the last decades due to increasing multidrug resistance demand innovative strategies for novel and effective antifungal drugs. Synergistic combinations of antifungals with non‐antifungal agents highlight a pragmatic strategy to reduce the development of drug resistance and potentially repurpose known compounds with other functions to bypass costly and time‐consuming novel drug development. [ABSTRACT FROM AUTHOR]

In this research, we will apply photoacoustic spectroscopy and evaluate bread added with turmeric (Curcuma longa Linnaeus) at different concentrations in relation to wheat flour weight (0, 1.25, 2.5, 5, and 10%). The amplitude of the photoacoustic signal was related to measures of antioxidant activity and evaluation of the sanitary quality and also, the texture, color, and sensory acceptability of the breads. It is shown that (i) the photoacoustic signal produced by bread significantly increases with the turmeric concentration, such that it raises more than 100% for a concentration of 10% at the wavelengths of 428 and 515 nm. (ii) The bread antioxidant activity is directly proportional to the level of photoacoustic signal at 515 nm and its value increases from 73.21 to 91.73%, when the concentration increases from 0 to 10%. (iii) The sanitary quality of bread added with 2.5% of turmeric is relatively higher than the ones obtained for other lower concentrations. No fungal colonies were observed in bread mixed with 2.5%, 5%, and 10%, after 6 days of storage. (iv) The addition of turmeric powder for bread making can slow down their textural changes (hardness, elasticity, cohesiveness, resilience, and chewiness) during storage. (v) Bread at 2.5 and 5% of turmeric concentration showed the yellowest color, while the one with a 10% concentration exhibited the most reddish color. Finally, through principal component analysis, it was possible to demonstrate that a concentration of either 5 or 10% of turmeric added to wheat flour could be used to improve its sanitary quality and antioxidant activity. [ABSTRACT FROM AUTHOR]

Curcumin, the active component of Curcuma longa L. (Zingiberaceae), exhibits a wide variety of biological activities including vasodilation and anti-inflammation. The relaxant effect of curcumin in tracheal smooth muscle (TSM) was not examined so far, thus, this study was designed to assess the relaxant effect of curcumin on rat TSM and examine the underlying mechanism(s) responsible for this effect. TSM was contracted by KCl (60 mM) or methacholine (10 μM), and cumulative concentrations of curcumin (12.5, 25, 50, and 100 mg/mL) or theophylline (0.2, 0.4, 0.6, and 0.8 mM, as positive control) were added to organ bath. The relaxant effect of curcumin was examined in non-incubated or incubated tissues with atropine (1 μM), chlorpheniramine (1 μM), indomethacin (1 μM), and papaverine (100 μM). In non-incubated TSM, curcumin showed significant relaxant effects on KCl-induced contraction in a concentration-dependent manner (p < 0.001 for all concentrations). The relaxant effects of curcumin 12.5, 25, and 50 mg/mL were significantly lower in atropine-incubated tissue compared to non-incubated TSM (p < 0.05 to p < 0.001). A significant difference was observed in EC50 between atropine-incubated (48.10 ± 2.55) and non-incubated (41.65 ± 1.81) tissues (p < 0.05). Theophylline showed a significant relaxant effect on both KCl and methacholine-induced contraction in a concentration-dependent manner (p < 0.001 for all cases). The results indicated a relatively potent relaxant effect of curcumin on TSM, which was less marked than the effect of theophylline. Calcium channel blocking and/or potassium channel opening properties of curcumin may be responsible for TSM relaxation. [ABSTRACT FROM AUTHOR]

Chronic low back pain (cLBP) that cannot be attributable to a specific pathoanatomical change is associated with high personal and societal costs. Still, the underlying mechanism that causes and sustains such a phenotype is largely unknown. Emerging evidence suggests that epigenetic changes play a role in chronic pain conditions. Using reduced representation bisulfite sequencing (RRBS), we evaluated DNA methylation profiles of adults with non-specific cLBP (n = 50) and pain-free controls (n = 48). We identified 28,325 hypermethylated and 36,936 hypomethylated CpG sites (p < 0.05). After correcting for multiple testing, we identified 159 DMRs (q < 0.01and methylation difference > 10%), the majority of which were located in CpG island (50%) and promoter regions (48%) on the associated genes. The genes associated with the differentially methylated regions were highly enriched in biological processes that have previously been implicated in immune signaling, endochondral ossification, and G-protein coupled transmissions. Our findings support inflammatory alterations and the role of bone maturation in cLBP. This study suggests that epigenetic regulation has an important role in the pathophysiology of non-specific cLBP and a basis for future studies in biomarker development and targeted interventions. [ABSTRACT FROM AUTHOR]

Poisonous animals imply a risk to human life, because their venom is a complex mixture of low molecular weight components, peptides and proteins. Hornets use the venom for self-defence, to repel intruders and to capture prey, but they can cause poisoning and allergic reactions to people. In particular, they seem to be a health problem in the countries where they are native due to their sting, which in the most severe cases can lead to severe or fatal systemic anaphylaxis. But this situation is being an emerging problem for new countries and continents because hornet incursions are increasing in the global change scenario, such as in Europe and America. Furthermore, 55 detailed cases of hornet sting were found in 27 papers during the current review where 36.4% died due to, mainly, a multi-organ failure, where renal failure and liver dysfunction were the most common complications. Moreover, the great taxonomic, ecological diversity, geographical distribution and the wide spectrum of pathophysiological symptoms of hornets have been the focus of new research. Considering this, the present systematic review summarizes the current knowledge about the components of Vespa venom and the epidemiology of its sting to serve as reference for the new research focused on the development of techniques for diagnosis, new drugs and treatments of its sting. [ABSTRACT FROM AUTHOR]

Objective: To investigate complement(C) factors(F) and their activation fragments expression in OA joint tissues. Design: Immunohistochemistry and quantitative imaging were performed to analyze C3, C4, and CF (factor) B expression on osteochondral biopsies (43 patients) collected during arthroplasty. Isolated chondrocytes and synoviocytes, cartilage and synovial tissues obtained from surgical specimens of OA patients (15 patients) were cultured with or without IL-1β. Real time PCR for CFB, C3, and C4 was performed. Culture supernatants were analyzed for C3a, C5a, CFBa, and terminal complement complex (TCC) production. Results: In osteochondral biopsies, C factor expression was located in bone marrow, in a few subchondral bone cells and chondrocytes. C3 was the most expressed while factor C4 was the least expressed factor. Gene expression showed that all C factors analyzed were expressed both in chondrocytes and synoviocytes. In chondrocyte cultures and cartilage explants, CFB expression was significantly higher than C3 and C4. Furthermore, CFB, but not C3 and C4 expression was significantly induced by IL-1β. As to C activation factors, C3a was the most produced and CFBa was induced by IL-1β in synovial tissue. TCC production was undetectable in isolated chondrocytes and synoviocytes cell culture supernatants, whereas it was significantly augmented in cartilage explants. Conclusion: C factors were locally produced and activated in OA joint with the contribution of all tissues (cartilage, bone, and synovium). Our results support the involvement of innate immunity in OA and suggest an association between some C alternative pathway component and joint inflammation. [ABSTRACT FROM AUTHOR]

The solubility of curcumin in the pure water subcritical and water–ethanol solution (water + (5–10) % (v/v) ethanol) subcritical is investigated for the first time. The design approach taken from this study is the response surface methodology due to the Box Behnken. The experiments were performed in the temperature range of (90–150) °C, (0–10) volumetric percent of ethanol and the flow rate of (0.2–0.8) ml/min. As the pressure effect is ignored in the subcritical conditions, the pressure is constant in 2 MP in the experiments. All analyses were carried out employing the high-performance liquid chromatography apparatus. The curcumin solubility data were correlated with the dielectric constant of solvent mixture. Curcumin solubility modeling in subcritical conditions was done due to cubic-plus-association equation of state. The present study indicated that the rise in temperature and ethanol percentage cause an increase in curcumin solubility. Other important finding was by increasing the flow rate, curcumin solubility rate increased with a very mild slope. The optimum conditions for the curcumin solubility were in the water flow rate of 0.8 ml/min, 10% (v/v) of ethanol, and the temperature of 150 °C. [ABSTRACT FROM AUTHOR]

Objective: To compare the unilateral signs of knee osteoarthritis (KOA) 30 and 60 days after anterior cruciate ligament transection (ACLT). Pain, gait function, synovial fluid inflammation, and histopathological changes in the synovial membrane were analyzed, as well as the interaction between the variables. Materials and methods: Male Wistar rats (n = 32; 219.2 ± 18.6 g) were randomly distributed into four groups of eight animals each. Two groups were submitted to unilateral ACLT surgery to induce KOA and analyzed after 30 (KOA30) and 60 days (KOA60). Two control groups (without surgery) were also assessed after the same time periods (C30 and C60). All the groups were evaluated before ACLT from the least to most stressful tests (skin temperature, mechanical response threshold, gait test, thermal response threshold, and joint swelling), as well as 30 and 60 days after surgery. After euthanasia, the synovial fluid and synovial membrane were collected. Results: Thirty days after ACLT, KOA30 showed decrease paw print area and mechanical response threshold, higher joint swelling, skin temperature, leukocyte count, cytokine levels, and synovitis score. No differences were found between KOA30 and KOA60. Conclusion: Our data showed that 30 days after ACLT is sufficient to induce signs of KOA in rats, such as pain, functional impairment, and synovial inflammation, suggesting that a shorter time period can be used as an experimental model. [ABSTRACT FROM AUTHOR]

Joint pain is a distressing symptom of arthritis, and it is frequently persistent even after treatments which reduce local inflammation. Continuous production of algogenic factors activate/sensitize nociceptors in the joint structures and contribute to persistent pain, a challenging and difficult condition to treat. TNF is a crucial cytokine for the pathogenesis of several rheumatic diseases, and its inhibition is a mainstay of treatment to control joint symptoms, including pain. Here, we sought to investigate the inflammatory changes and the role of TNF in dorsal root ganglia (DRG) during persistent hypernociception after the resolution of acute joint inflammation. Using a model of antigen-induced arthritis, the peak of joint inflammation occurred 12–24 h after local antigen injection and was characterized by an intense influx of neutrophils, pro-inflammatory cytokine production, and joint damage. We found that inflammatory parameters in the joint returned to basal levels between 6 and 8 days after antigen-challenge, characterizing the resolving phase of joint inflammation. Mechanical hyperalgesia was persistent up to 14 days after joint insult. The persistent nociception was associated with the inflammatory status of DRG after cessation of acute joint inflammation. The late state of neuroinflammation in the ipsilateral side was evidenced by gene expression of TNF, TNFR2, IL-6, IL-1β, CXCL2, COX2, and iNOS in lumbar DRG (L3-L5) and leukocyte adhesion in the lumbar intumescent vessels between days 6 and 8. Moreover, there were signs of resident macrophage activation in DRG, as evidenced by an increase in Iba1-positive cells. Intrathecal or systemic injection of etanercept, an agent clinically utilized for TNF neutralization, at day 7 post arthritis induction, alleviated the persistent joint hyperalgesia by specific action in DRG. Our data suggest that neuroinflammation in DRG after the resolution of acute joint inflammation drives continuous neural sensitization resulting in persistent joint nociception in a TNF-dependent mechanism. [ABSTRACT FROM AUTHOR]

Introduction: Neurodegeneration is the term describing the death of neurons both in the central nervous system and periphery. When affecting the central nervous system, it is responsible for diseases like Alzheimer's disease, Parkinson's disease, Huntington's disorders, amyotrophic lateral sclerosis, and other less frequent pathologies. There are several common pathophysiological elements that are shared in the neurodegenerative diseases. The common denominators are oxidative stress (OS) and inflammatory responses. Unluckily, these conditions are difficult to treat. Because of the burden caused by the progression of these diseases and the simultaneous lack of efficacious treatment, therapeutic approaches that could target the interception of development of the neurodegeneration are being widely investigated. This review aims to highlight the most recent proposed novelties, as most of the previous approaches have failed. Therefore, older approaches may currently be used by healthcare professionals and are not being presented.Methods: This review was based on an electronic search of existing literature, using PubMed as primary source for important review articles, and important randomized clinical trials, published in the last 5 years. Reference lists from the most recent reviews, as well as additional sources of primary literature and references cited by relevant articles, were used.Results: Eighteen natural pharmaceutical substances and 24 extracted or recombinant products, and artificial agents that can be used against OS, inflammation, and neurodegeneration were identified. After presenting the most common neurodegenerative diseases and mentioning some of the basic mechanisms that lead to neuronal loss, this paper presents up to date information that could encourage the development of better therapeutic strategies.Conclusions: This review shares the new potential pharmaceutical and not pharmaceutical options that have been recently introduced regarding OS and inflammatory responses in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Purpose: The complex nature of cancer-induced bone pain (CIBP) has led to investigation into cancer-targeted therapies. This has involved targeting glutamate release from the tumor, secreted as a byproduct of antioxidant responses and metabolic disruption. Cancer cells undergo many metabolic changes that result in increased glutamine metabolism and subsequently the production of glutamate. Glutaminase (GLS) is the enzyme that mediates the conversion of glutamine to glutamate and has been shown to be upregulated in many cancer types including malignancies of the breast. This enzyme, therefore, represents another potential therapeutic target for CIBP, one that lies upstream of glutamate secretion. Methods: A recently developed inhibitor of GLS, CB-839, was tested in an animal model of CIBP induced by intrafemoral MDA-MB-231 xenografts. CIBP behaviors were assessed using Dynamic Weight Bearing and Dynamic Plantar Aesthesiometer readings of mechanical hyperalgesia and allodynia. Results: CB-839 failed to modulate any of the associated nociceptive behaviors induced by intrafemoral MDA-MB-231 tumor growth. Further investigation in vitro revealed the sensitivity of the drug is dependent on the metabolic flexibility of the cell line being tested which can be modulated by cell culture environment. Conclusion: Adaptation to metabolic disturbances may explain the failure of CB-839 to exhibit any significant effects in vivo and the metabolic flexibility of the cell line tested should be considered for future investigations studying the metabolic effects of glutaminase inhibition. [ABSTRACT FROM AUTHOR]

The central nervous system (CNS) constitutively expresses complement (C) membrane receptors and complement proteins, including the component C5a. This is a crucial terminal effector of the C cascade, mostly involved in pain and neuroinflammatory conditions. Aberrant activation of C5a protein and its receptor C5aR has been reported to play a critical role in neurodegenerative diseases, with important clinical consequences. Here we have investigated the effects of DF3016A, a novel selective C5aR antagonist, able to penetrate the blood-brain barrier (BBB), on cortical neurons exposed to oxygen-glucose deprivation-reoxygenation (OGD/R), a neuroinflammation-related process. We demonstrated that a mild ischemic insult induces an early upregulation of C5aR associated with the over-production of pro-inflammatory cytokines and the over-expression of the transcriptional regulatory factor miR-181. Furthermore, we report the first experimental evidence of the effect of DF3016A, modulating complement component C5a, on neurons in a model of injury. Interestingly, DF3016A protects neuronal viability by restoring intracellular calcium levels, thus opposing the increase in pro-inflammatory cytokine levels and miR-181 expression. Based on our results, we suggest that DF3016A is a novel C5aR antagonist promoting protective effects against OGD/R-induced damage that could be a new therapeutic approach to controlling CNS neuroinflammatory conditions. [ABSTRACT FROM AUTHOR]