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The majority of conventional osteoarthritis (OA) treatments are based on molecular adjustment of certain signaling pathways associated with osteoarthritis (OA) pathogenesis, however there is a significant need to search for more effective and safe treatments. This study centers around formulating Aceclofenac (ACF) with high bioavailability in combination with Citronellol oil and collagen. The optimal concentrations of Citronellol oil/D-Limonene oil, Tween 80, and Transcutol HP were determined using a pseudoternary phase diagram. The formulated nanoemulsions were studied for thermophysical stability. Thermodynamically stable formula were analyzed for droplet size, zeta potential, and in-vitro permeation. Then, collagen based nanoemulsion were prepared to capitalize on its efficacy in reducing osteoarthritis side effects and characterized for nano size properties. Formulae F10 and F10C were chosen as optimum nanosize formula. Hense, they were prepared and characterized as nanoemulgel dosage form. The nanoemulgel formulae F10NEG1 and F10CNEG1 showed reasonable viscosity and spreadability, with complete drug release after 4 h. These formulae were chosen for further In vivo anti-OA study. Collagen based ACF/citronellol emugel were able to modulate HMGB-1/RAGE/NF-κB pathway, mitigating the production of inflammatory cytokine TNF-α. They were also able to modulate Klotho and miR-499, reducing serum CTXII and COMP, by reducing the cartilage destruction. Histological investigations validated the efficacy, safety, and superiority of Aceclofenac in combination with Citronellol oil and collagen (F10CNEG1) over solo the treated group (F10NEG1 and blank). Hence, the findings of the current work encourage the use of this promising combined formula in treatment of OA patients. [ABSTRACT FROM AUTHOR]

Introduction: We investigated the efficiency of high mobility group box-1 protein (HMGB-1) in differentiation of asymptomatic knee prosthesis, and periprosthetic joint infection and aseptic loosening causing painful knee prosthesis. Materials and Methods: The data of patients who consulted our clinic for checking after total knee arthroplasty surgery were recorded prospectively. Blood levels of CRP, ESR, WBC, and HMGB-1 were recorded. Patients whose examination and routine tests were within normal limits comprised group I, asymptomatic total knee arthroplasty (ATKA). Painful patients with abnormal test results underwent three phase bone scintigraphy for further investigation Patients with periprosthetic joint infection (PJI) and aseptic loosening (AL) according to scintigraphy comprised group II and group III, respectively. The mean values of HMGB-1 and cut-off values according to the groups and their correlations with other inflammatory parameters were determined. Results: Seventy-three patients were included in the study. Significant differences were observed in three groups, in terms of CRP, ESR, WBC, and HMGB-1. The cut-off value of HMGB-1 was determined as 15.16 ng/ml between ATKA and PJI, 16.92 ng/ml between ATKA and AL, and 27.87 ng/ml between PJI and AL, respectively. Accordingly, the sensitivity, and specificity of HMGB-1 in differentiation of ATKA and PJI were 91%, 88%, and in differentiation of ATKA and AL were 91%, 96%, and in differentiation of PJI and AL were 81%, 73%, respectively. Conclusion: HMGB-1 may be utilized as an additional blood test in the differential diagnosis of problematic knee prosthesis patients. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to explore the mechanism of Nobiletin attenuating Alzheimer's disease (AD) by inhibiting neuroinflammation. Methods: The expression of inflammatory cytokines and HMGB-1 in serum of AD patients were examined. Microglia (MGs) were treated with different doses of Nobiletin before LPS and Nigericin induction. Cell viability and apoptosis were determined by CCK-8 and TUNEL assays, respectively. APP/PS1 mice were gavaged with Nobiletin, and Morris water maze (MWM) was established to record swimming speed, escape latency, the number of platform crossings, and time spent in the platform quadrant. MGs activation in brain tissues was evaluated by immunofluorescence. The expression of pyroptosis-related proteins, inflammatory cytokines, and HMGB-1 was determined in the hippocampus and MGs. Results: The levels of inflammatory cytokines and HMGB-1 were high in serum of AD patients. Treatment with different concentrations of Nobiletin prominently enhanced cell viability and reduced apoptosis and the expression of inflammatory cytokine and pyroptosis-related proteins in LPS + Nigericin-induced MGs. Gavage of different doses of Nobiletin into APP/PS1 mice shortened the escape latency in mice, diminished MGs activation in brain tissues, and remarkably elevated the number of platform crossings and the time spent in the platform quadrant without obvious change in swimming speed, suggesting that Nobiletin improved the spatial learning and memory abilities in APP/PS1 mice. The expression of pyroptosis-related proteins, HMGB-1, and inflammatory cytokines was decreased dramatically by Nobiletin in the hippocampus of APP/PS1 mice. Conclusions: Nobiletin can inhibit neuroinflammation by inhibiting HMGB-1, pyroptosis-related proteins, and inflammatory cytokines, thus mitigating AD. [ABSTRACT FROM AUTHOR]

Urothelial carcinoma of bladder (UBC), a highly prevalent urological malignancy associated with high mortality and recurrence rate. Standard diagnostic method currently being used is cystoscopy but its invasive nature and low sensitivity stresses for identifying predictive diagnostic marker. Autophagy, a cellular homeostasis maintaining process, is usually dysregulated in cancer and its role is still enigmatic in UBC. In this study, 30 UBC patients and healthy controls were enrolled. Histopathologically confirmed tumor and adjacent normal tissue were acquired from patients. Molecular expression and tissue localization of autophagy-associated molecules (HMGB-1, RAGE, beclin, LC-3, and p62) were investigated. Serum HMGB-1 concentration was measured in UBC patients and healthy controls. ROC curves were plotted to evaluate diagnostic potential. Transcript, protein, and IHC expression of HMGB-1, RAGE, beclin, and LC-3 displayed upregulated expression, while p62 was downregulated in bladder tumor tissue. Serum HMGB-1 levels were elevated in UBC patients. Transcript and circulatory levels of HMGB-1 showed positive correlation and displayed a positive trend with disease severity. Upon comparison with clinicopathological parameters, HMGB-1 emerged as molecule of statistical significance to exhibit association. HMGB-1 exhibited optimum sensitivity and specificity in serum. The positive correlation between tissue and serum levels of HMGB-1 showcases serum as a representation of in situ scenario, suggesting its clinical applicability for non-invasive testing. Moreover, optimum sensitivity and specificity displayed by HMGB-1 along with significant association with clinicopathological parameters makes it a potential candidate to be used as diagnostic marker for early detection of UBC but requires further validation in larger cohort. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a degenerative disease characterized by the destruction of cartilage. The greatest risk factors for the development of OA include age and obesity. Recent studies suggest the role of inflammation in the pathogenesis of OA. The two most common locations for OA to occur are in the knee and hip joints. The knee joint experiences more mechanical stress, cartilage degeneration, and inflammation than the hip joint. This could contribute to the increased incidence of OA in the knee joint. Damage-associated molecular patterns (DAMPs), including high-mobility group box-1, receptor for advanced glycation end products, and alarmins (S100A8 and S100A9), are released in the joint in response to stress-mediated chondrocyte and cartilage damage. This facilitates increased cartilage degradation and inflammation in the joint. Studies have documented the role of DAMPs in the pathogenesis of OA; however, the comparison of DAMPs and its influence on OA has not been discussed. In this study, we compared the DAMPs between OA knee and hip joints and found a significant difference in the levels of DAMPs expressed in the knee joint compared to the hip joint. The increased levels of DAMPs suggest a difference in the underlying pathogenesis of OA in the knee and the hip and highlights DAMPs as potential therapeutic targets for OA in the future. [ABSTRACT FROM AUTHOR]

Purpose: Traumatic insults result in an altered inflammatory response, in which alarmins release has a central role. The impact of haemorrhagic shock intensity on the long-term kinetics of alarmins is not yet fully elucidated. We investigated these aspects in a combined trauma (chest, abdominal, and extremities injury) porcine model with different severities and durations of haemorrhagic shock. Methods: After induction of combined trauma (tibia fracture, lung contusion, and liver laceration), haemorrhagic shock was induced at different intensities: moderate haemorrhage (MH; n = 15): mean arterial pressure (MAP) <30 ± 5 mmHg [maximum loss of total blood volume (TBV): 45 %] for 90 min, and severe haemorrhage (SH; n = 10): MAP <25 ± 5 mmHg (TBV 50 %) for 120 min. Resuscitation was performed using a standardized crystalloid infusion protocol. Animals were mechanically ventilated and underwent ICU-monitoring for 48 h (MH) and 48.5 h (SH). Blood samples were collected over the clinical time course, and systemic levels of serum alarmins [High-Mobility Group Protein B-1 (HMGB-1) and Heat Shock Protein 70 (HSP70)] were measured using an ELISA kit. Results: Heart rate, systemic blood pressure, lactate, and base excess were significantly altered as a function of haemorrhagic shock in both trauma groups (MH and SH). Systemic HMGB-1 levels were significantly elevated in both trauma groups when compared to the sham group. Haemorrhagic shock severity and duration were positively correlated with HMGB-1 levels and compared to baseline values, concentrations remained significantly increased in SH when compared to MH. On the other hand, we observed a significant decrease in the systemic HSP70 levels of trauma groups (MH, and SH) when compared to the sham group, which was significantly decreased compared to baseline values in SH over the entire time course. Conclusion: Our data show that haemorrhagic shock duration and severity affect the systemic levels of HMGB-1 and HSP70. This early alarmins release after trauma can be used to guide the treatment strategies (e.g. surgical procedures) of polytrauma patients. [ABSTRACT FROM AUTHOR]

Studies have shown that LPS-preconditioned tolerant state could protect against brain injury to subsequent challenges. We hypothesized astrocytes were directly involved in the readjustment to confer neuroprotective effects with LPS pretreatment. High-mobility group box 1(HMGB-1) from LPS-preconditioned astrocytes, presumably serving as a positive regulator, might contribute to the favorable preconditioned effects. Furthermore, a potential cellular pathway (PI3K/AKT pathway), has been proposed for the active regulation of LPS-primed reactive astrocytes to secrete HMGB-1. In the present study, we used a low concentration of LPS to directly prime the astrocytes in vitro, and the subsequent astrocytic reactions, including cytokine secretion, the expression of transcription factors, and the release of HMGB-1 were examined after the blockade of the PI3K pathway. The data showed that LPS preconditioning could reduce some capacity of astrocytes to subsequent challenge in vitro. PI3K/AKT pathway was partially involved in the modulation of the release HMGB-1 from reactive astrocytes. These findings offer direct evidence supporting the flexible roles of astrocytes in mediating LPS-primed neuroprotection, and highlight additional targets for future attempts to modify the protective effects of astrocytes through LPS preconditioning. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate the protective effect of recombinant human brain natriuretic peptide (rhBNP) on endotoxin-induced acute kidney injury (AKI) in canine model of septic shock and its potential mechanisms. Dogs with endotoxin-induced septic shock were subjected to intravenous infusion of saline solution or rhBNP at the concentrations of 5 μg/kg (low-dose intervention group) or 10 μg/kg (high-dose intervention group). At 0, 2, 4, 8, and 12 h, the systemic vascular resistance index (SVRI) as well as serum levels of high mobility group box 1 protein (HMGB-1) and creatinine were measured, and kidney tissue samples were taken for histological examination. We have found that low and high doses of rhBNP could significantly reduce kidney tissue damage, such as tubular epithelial swelling and atrophy, and interstitial cell swelling in response to LPS injection in the dog sepsis models. rhBNP administration significantly reduced SVRI and serum levels of creatinine in dogs with LPS-induced sepsis in a dose-dependent manner, and attenuated the rise in the circulating HMGB-1. In conclusion, these findings suggest that rhBNP may exert dose-dependent protective effect on kidney tissue with endotoxin-induced injury, and this effect may be associated with the changes in blood levels of HMGB-1. rhBNP may be considered as therapeutic agents for treating sepsis-induced AKI. [ABSTRACT FROM AUTHOR]

Extracellular high-mobility group box-1 (HMGB-1) has been implicated in the inflammation response leading to the precancerous lesions of non-small cell lung cancer (NSCLC). However, the role of HMGB-1 in the inflammation response in normal human bronchial epithelial (NHBE) cells and its underlying mechanisms were still not fully understood. In this study, the inflammation response in NHBE cells was stimulated by 2.5, 5, and 10 μg/ml HMGB-1. However, the receptor for advanced glycation end products (RAGE) blocker RAGE-Ab (5 μg/ml) or 10 μM c-Jun N-terminal kinases (JNK) inhibitor SP600125 could inhibit HMGB1-induced the release of inflammation cytokines including TNF-α, IL-8, IL-10, and MCP-1 in a dose-dependent manner. Furthermore, HMGB1-induced RAGE protein expression, JNK and NF-κB activation were attenuated by the pretreatment with RAGE-Ab or JNK inhibitor SP600125 in Western blot analysis. Our data indicated that HMGB-1 induced inflammation response in NHBE cells through activating RAGE/JNK/NF-κB pathway. HMGB-1 could act as a therapeutic target for inflammation leading NHBE cells to the precancerous lesions of NSCLC. [ABSTRACT FROM AUTHOR]

Myeloid differentiation primary response protein 88 (Myd88) is a vital factor for inflammation and immunity, and high-mobility group box 1 protein (HMGB-1) can be released from neurons after injury and may contribute to the initial stages of inflammatory response. Therefore, the current study was intended to investigate the expression of Myd88 in cultured neurons following recombinant HMGB-1 (rHMGB-1) addition and to clarify the potential role of Myd88 after neuron injury in vitro. The cultured neurons were randomly divided into six groups: control group and rHMGB-1 groups at hours 1, 6, 12, 24, and 48. The cultured neurons in rHMGB-1 groups were subjected to rHMGB-1 addition. The expression of Myd88 was assessed by quantitative real-time polymerase chain reaction (PCR), Western blotting and immunofluorescence, and nuclear factor kappa B (NF-κB) DNA-binding activity was detected by electrophoretic mobility shift assay, and the levels of tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β) were measured by quantitative real-time PCR. The elevated mRNA and protein levels of Myd88, peaking at 24 h, were detected after rHMGB-1 addition. NF-κB, TNF-α, and IL-1β also ascended significantly after rHMGB-1 addition. Interestingly, Myd88 increasingly expressed in a parallel time course to the upregulation of NF-κB, TNF-α, and IL-1β. These findings indicated a possible role of Myd88 in the inflammatory response after neuron injury, and might provide an attractive therapeutic approach of targeting the Myd88 cascade to achieve better outcomes for patients with central nervous system injury. [ABSTRACT FROM AUTHOR]

High mobility group box protein-1 (HMGB-1) was recently identified as a new type of inflammatory cytokine. Inflammation can lead to malnutrition to some extent. Our study was aimed to clarify the relationship between serum HMGB-1 level with microinflammatory state and nutritional status in continuous ambulatory peritoneal dialysis (CAPD) patients. Patients in the treatment of maintenance of peritoneal dialysis for >6 months were included. HMGB-1, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunosorbent assay (ELISA). High-sensitivity C-reactive-protein (hs-CRP), prealbumin (PA), serum albumin (S-Alb), hemoglobin (Hb), subjective global nutritional assessment (SGA), and CAPD presents' urea clearance rate (Kt/V), creatinine clearance (CrCl), residual glomerular filtration rate (rGFR), and dialysate-to-plasma ratio of creatinine after 4 h (D/P) were analyzed. The Independent-samples t test and Pearson's rank correlation test were used. Serum HMGB-1, IL-6, and TNF-α of CAPD patients were significantly higher than in the control group ( P < 0.05); Serum HMGB-1 levels had positive relationships with TNF-α ( r = 0.730, P < 0.01), hs-CRP ( r = 0.361, P < 0.01), and IL-6 ( r = 0.865, P < 0.01), and had negative relationships with Hb ( r = −0.59, P < 0.01), Alb ( r = −0.34, P < 0.05), and PA ( r = −0.44, P < 0.01); no significant relationships were found between serum HMGB-1 with SGA, peritoneal dialysis age, Kt/V, CrCl, rGFR, and D/P. Our study revealed that HMGB-1 was elevated significantly in CAPD patients and correlated with indicators of inflammation and malnutrition. Serum HMGB-1 could be used as a marker for evaluating inflammation and malnutrition in CAPD patients. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a complex disease resulting from inflammatory responses of the immune system against several autoantigens. Inflammation is conditioned by the continuous presence of autoantibodies and leaked autoantigens, e.g. from not properly cleared dying and dead cells. Various soluble molecules and biophysical properties of the surface of apoptotic cells play significant roles in the appropriate recognition and further processing of dying and dead cells. We exemplarily discuss how Milk fat globule epidermal growth factor 8 (MFG-E8), biophysical membrane alterations, High mobility group box 1 (HMGB1), C-reactive protein (CRP), and anti-nuclear autoantibodies may contribute to the etiopathogenesis of the disease. Up to date knowledge about these key elements may provide new insights that lead to the development of new treatment strategies of the disease. [ABSTRACT FROM AUTHOR]