Nuclear Factor Kappa Beta Pathway Research Articles

Secretome Hypoxia Mesenchymal Stem Cells Inhibited Ultraviolet Radiation by Inhibiting Interleukin-6 through Nuclear Factor-Kappa Beta Pathway in Hyperpigmentation Animal Models

UVB radiation is the main factor causing hyperpigmentation. Secretome hypoxic mesenchymal stem cells (S-HMSCs) contain bioactive soluble molecules such as growth factors and anti-inflammatory cytokines that can prevent melanin synthesis and induce collagen formation. However, the role of S-HMSCSs on IL-6, p50, and p65 gene expression in hyperpigmentation is still unclear. This study aimed to determine the effect of administration of S-HMSCSs gel on the expression of IL-6, p50, and p65 in a hyperpigmented rat skin model induced by UVB light exposure. Twenty-five male Wistar rats of hyperpigmented were created as an animal model under exposed to UVB 6 times in 14 days at 302 nm with a MED of 390 mJ/cm2. The animal was randomly assigned into five groups consisting of two treatment groups (treated by S-HMSCs at a 100µL as T1 and 200µL as T2 on bases gel) for 14 days, control groups (UVB-irradiation), sham (negative control), and base gel groups. On the 14th day, IL-6, p50, and p65 were terminated and analyzed using qRT-PCR. Statistical analysis will perform using one way ANOVA followed with post hoc LSD test. Analysis of IL-6 (8.59± 3.32), p50 (4.35±2.27), and p65 (4.09±1.82) gene expression in the treatment group decreased along with the increase in the concentration of S-MSCs compared to the control group. In conclusion, the administration of S-HMSCs gel is expected to affect the speed of decreasing the hyperpigmentation process significantly.

PS-B08-9: INHIBITION OF PERIOSTIN PROTECTED FROM EXACERBATION OF INFLAMMATION IN RHABDOMYOLYSIS-INDUCED ACUTE KIDNEY INJURY

Objective: Rhabdomyolysis is the breakdown of damaged skeletal muscle and the leakage of muscle-cell contents, including myoglobin, and other sarcoplasmic proteins into the circulation. These products may be filtered through the glomeruli, leading to acute kidney injury (AKI) via several mechanisms, such as inflammation and intratubular obstruction secondary to protein precipitation. New therapeutic strategy to lessen AKI are urgently needed. Thus far, several cellular pathways, nuclear factor kappa beta (NF-KB) as well as including pro-inflammatory effects on epithelial and tubular epithelial cells, have been identified as the major avenues for the initiation of the matrix-producing cells in AKI. Recently, it is suggested that periostin, extracellular matrix, is involved in the development of inflammation through the modulation of NF-KB pathway. However, periostin on the progression of the inflammation protection in AKI due to rhabdomyolysis is unclear. This study aimed to investigate the role of periostin in a rhabdomyolysis mice model of AKI. Design and method: In vivo, rhabdomyolysis-induced AKI was created by an intramuscular injection of 50% glycerol (5 mg/kg body weight). The expression level of periostin during the progression of acute renal failure after glycerol intramuscular injection for C57BL/6J wild type (WT) mice model was investigated. The mice were sacrificed at 72 hours after glycerol injection. We have developed periostin null mice to examine the role of periostin on acute renal failure. The role of periostin were further investigated through in vitro methods. In vitro, the development of renal inflammation is associated with NF-KB pathway. To investigate the function of periostin, we administrated Hemin(100uM) on NIH-3T3 fibroblast cells and the subsequent signaling pathways was examined. Results: The expression of periostin was highly increased, peaking at approximately 72 hours after gycerol injection. Inflammation-associated mRNA such as Monocyte Chemotactic Protein-1, tumor necrosis factor-alpha and IL6 expression and tubular injury score in H-E staining was more reduced in periostin null mice than WT mice at 72 hours after gycerol injection. Finally, an intraperitoneal injection of periostin antibody suppressed the mortality. These findings suggest a causal link between periostin and inflammation in AKI induced by rhabdomyolysis. In addition, an intraperitoneal injection of antibody for periostin antibody might be a new therapeutic strategy against the development of AKI induced by rhabdomyolysis. Conclusions: Periostin were highly expressed in kidney via rhabdomyolysis, and were a positive regulator of AKI. Targeting periostin might offer a new therapeutic strategy against the development of renal failure.

Estimation of L-carnitine levels in diabetic completely edentulous patients for implant diagnosis: A cross-sectional study

Background: Carnitine is effective in preventing the accumulation of end products related to lipid peroxidation due to its anti-inflammatory and antioxidant effects. Carnitine also exerts a significant anti-inflammatory role through the downregulation of the nuclear factor kappa beta pathway, which leads to a decrease in the expression of pro-inflammatory cytokines. The aim of the study was to estimate the L-carnitine (L-C) levels in diabetic completely edentulous patients. Materials and Methods: A cross-sectional study was conducted after the selection of 60 samples based on the inclusion and exclusion criteria. The collected saliva samples were utilized to measure the levels of L-C using the sandwich enzyme-linked immunosorbent assay (ELISA) method. One hundred microliters of sample was applied to a particular row of wells and incubated for an hour as part of the sandwich ELISA procedure. After the wells had been cleaned, a second batch of monoclonal L-C was added, and they were once more incubated for an hour. The horseradish peroxidase substrate was then applied after washing the second batch as well. To allow the blue-to-yellow color transition, the wells were kept steady. Following the observation of the color shift, the OD was measured, and the concentration was determined using the sandwich ELISA kit's standard curve as an intercept. The data were statistically analyzed using the independent t-test (significant level P < 0.05) and were tabulated. Results: The L-C levels have higher levels in nondiabetic patients than in diabetic patients. The difference in the baseline mean value between the groups was statistically significant (P = 0.00). Although it is statistically significant (P = 0.00), the mean value for diabetic individuals is 0.19 as opposed to 0.29 for nondiabetic patients. Conclusion: Based on the findings, it can be concluded that L-C improves insulin sensitivity and glucose disposal in diabetic completely edentulous patients.

Blocking Periostin Prevented Development of Inflammation in Rhabdomyolysis-Induced Acute Kidney Injury Mice Model.

Rhabdomyolysis is the collapse of damaged skeletal muscle and the leakage of muscle-cell contents, such as electrolytes, myoglobin, and other sarcoplasmic proteins, into the circulation. The glomeruli filtered these products, leading to acute kidney injury (AKI) through several mechanisms, such as intratubular obstruction secondary to protein precipitation. The prognosis is highly mutable and depends on the underlying complications and etiologies. New therapeutic plans to reduce AKI are now needed. Up to now, several cellular pathways, with the nuclear factor kappa beta (NF-kB), as well as the proinflammatory effects on epithelial and tubular epithelial cells, have been recognized as the major pathway for the initiation of the matrix-producing cells in AKI. Recently, it has been mentioned that periostin (POSTN), an extracellular matrix protein, is involved in the development of inflammation through the modulation of the NF-kB pathway. However, how POSTN develops the inflammation protection in AKI by rhabdomyolysis is uncertain. This study aimed to investigate the role of POSTN in a rhabdomyolysis mice model of AKI induced by an intramuscular injection of 50% glycerol. In vivo, we performed an intramuscular injection of 50% glycerol (5 mg/kg body weight) to make rhabdomyolysis-induced AKI. We examined the expression level of POSTN through the progression of AKI after glycerol intramuscular injection for C57BL/6J wildtype (WT) mice. We sacrificed mice at 72 h after glycerol injection. We made periostin-null mice to examine the role of POSTN in acute renal failure. The role of periostin was further examined through in vitro methods. The development of renal inflammation is linked with the NF-kB pathway. To examine the POSTN function, we administrated hemin (100 μM) on NIH-3T3 fibroblast cells, and the following signaling pathways were examined. The expression of periostin was highly increased, peaking at about 72 h after glycerol injection. The expression of inflammation-associated mRNAs such as monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-a) and IL-6, and tubular injury score in H-E staining were more reduced in POSTN-null mice than WT mice at 72 h after glycerol injection. POSTN was highly expressed in the kidney through rhabdomyolysis and was a positive regulator of AKI. Targeting POSTN might propose a new therapeutic strategy against the development of acute renal failure.

Anesthetic concerns in recipients of hematopoietic stem cell transplant.

Dear Editor, Since the advent of bone marrow transplant in 1957, our understanding of the biology behind Hematopoietic Stem Cell Transplant (HSCT) has improved[1] and almost 50,000 HSCT take place globally in a year.[2] Although anesthetic concerns of patients undergoing solid organ transplantation have been addressed, there is a dearth of literature relating to HSCT, especially after the recent advancements like targeted therapy.[3,4] HSCT entails the regeneration of different blood cell lineages from donor stem cells and embarks on the interplay between recipient T lymphocytes, natural killer (NK) cells and donor antigen presenting cells (APC) and lymphocytes. Allogenic transplant brings forth graft vs. tumor effect (GVT) which helps to prevent recurrences but is shadowed by the graft vs. host disease (GVHD), necessitating chronic immunosuppression. Post HSCT patients are at increased risk of opportunistic infections, especially before engraftment and subtle signs of infections may be missed in the preoperative period as well as there may be delayed wound healing after surgery. While exaggerated increase in host immunity may enhance GVHD, overt diminution by immunosuppressant may lead to secondary infections and reactivation of cytomegalovirus. Therefore, it is prudent to delay elective surgeries before engraftment and while the patient is on immune-modulators.[5] Moreover, anesthesiologist should be aware of long-term adverse effects of chemotherapeutic drugs including potential difficult airway due to gum hypertrophy (cyclosporine) and lymph node enlargement as part of post-transplant lymphoproliferative disorder (PTLD). Acute GVHD may involve different organ systems, leading to potentially dreaded complications like acute lung injury, veno-occlusive disease of liver, thrombotic micro angiopathy (TMA) which should be evaluated during the pre-anesthetic check-up.[5] Surgical stress leads to a temporary state of immunosuppression via various mechanisms like raised catecholamines, angiogenic factors, matrix metalloproteinases (MMPs) and attenuated NK cell activity and cell mediated immunity (CMI). Volatile agents, especially isoflurane may promote tumor growth and spread by reducing NK cell activity, T cell depletion, increased angiogenesis by up-regulation of hypoxia inducible factor (HIF-1 alpha), whereas N2O causes bone marrow suppression. However, sevoflurane was found to stabilize the anti-cancer gene P38. Similar to inhaled agents, ketamine and thiopentone induces T cell apoptosis and NK cell underactivity. Propofol appears to be beneficial by reducing angiogenesis and maintaining T cell activity. Despite report showing impairment of macrophage-monocyte function, midazolam appears to be safer. Action of muscle relaxants may get prolonged due to immunomodulators like cyclosporine, as seen in renal transplant recipients.[6] Although anecdotal reports showed that IV opioids reduced NK cell, T cell and TLR (Toll like Receptor) activity on macrophage, it might enhance tumor lysis by stabilizing P53 and P38 and induce tumor death via NF-kB (nuclear factor kappa beta) and Fas-FasL pathway. Thus, immunomodulating effects of opioids are dose and concentration dependent and judicial perioperative analgesia by opioids seems logical.[7] Whenever feasible, use of regional anesthesia must be emphasized as local anesthetics increase local NK cell activity. Propofol along with paravertebral block have been found to be associated with reducing tumor burden in ER-negative breast cancer. Specific concerns of immune-modulators are provided in Table 1 and perioperative concerns are summarized in Table 2.Table 1: Side effects of commonly used agents and their concernsTable 2: Perioperative concerns in a nutshellInduction by propofol/etomidate, followed by maintenance with total intravenous anesthesia (TIVA) with propofol, intermediate acting muscle relaxants with minimal organ dependent metabolism (e.g., atrcurium, cisatracurium) and use of regional anesthesia may be considered as preferred techniques of choice. With the growing number of HSCTs, the authors feel the need for renewed interest and good quality research in this area. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Efficacy of green tea, its polyphenols and nanoformulation in experimental colitis and the role of non-canonical and canonical nuclear factor kappa beta (NF-kB) pathway: a preclinical in-vivo and in-silico exploratory study

NF-kB plays a major role in the aetiopathogenesis of inflammatory-colitis. In this study, we evaluated the efficacy of green tea and its polyphenols and their nanoformulation in Tri-Nitro Benzene Sulfonic acid (TNBS) induced colitis in in-vivo system (Rat) and the involvement of non-canonical and canonical NF-kB pathway in green tea mediated protection (in-silico platform). We used the Wister rat model of TNBS-induced colitis. Rats were grouped into eleven groups (six animals each) and administered vehicle (ethanol), TNBS, Epicatechin (EC), Epigallocatechin (EGC), Epicatechin-gallate (ECG), Epigallocatechin-gallate (EGCG), sulfasalazine, green tea, EGCG + sulfasalazine, nano-EGCG and nano-EGCG + sulfasalazine for 14 days after induction of colitis. Colonic tissue was evaluated for the level of malondialdehyde, myeloperoxidase activity, catalase, reduced glutathione, glutathione peroxidase, IL-6, TNF-α, IL-1β, NF-κB and morphological and histopathological evidence of damage. In the in-silico part, molecular docking and dynamic simulation study of EGCG was done against different targets in NF-kB for detailed evaluation of the role of non-canonical and canonical NF-KB pathway. In our study, EGCG reduced colonic inflammation, markers of oxidative stress, TNF-α, NF-κB, IL-1β and IL-6. Nano-EGCG + sulfasalazine was more efficacious when compared to EGCG + sulfasalazine. In molecular docking and molecular dynamic simulation studies, EGCG showed a good binding profile to the inhibitor binding sites of IKK-beta, IKK-alpha and NIK. Thus, it can be concluded that EGCG showed protective action in experimental colitis acting through both non-canonical and canonical NF-kB pathway. Nano-EGCG + sulfasalazine combination showed better protection than nano-EGCG alone. Communicated by Ramaswamy H. Sarma

Gene variants in the NF-KB pathway (NFKB1, NFKBIA, NFKBIZ) and risk for early-onset coronary artery disease

The nuclear-factor kappa-beta (NF-KB) is a driver of inflammation, and plays an important role in the pathogenesis of atherosclerosis and coronary artery disease (CAD). Early-onset CAD is defined as a coronary ischaemic episode at an age ≤55 years, and in our population was strongly associated with male sex and smoking. Our aim was to determine whether common variants in three NF-KB genes were associated with early-onset CAD. We studied 609 patients with early-onset CAD and 423 healthy controls, all male. Allele and genotype frequencies for the NFKB1 rs28362491 (-94 delATTG) and NFKBIA rs8904 were not significantly different between the two groups. For the NFKBIZ rs3217713, the deletion allele was significantly more frequent in the patients than in controls (0.27 vs. 0.22; p = 0.004). Deletion-carriers were more frequent in the patients (p < 0.001), with an OR = 1.48 (95%CI = 1.15–1.90). We performed a multiple logistic regression (linear generalized model) with smoking, hypercholesterolemia, type 2 diabetes, hypertension, and the rs3217713 deletion carriers remained significantly associated with early-onset CAD (p = 0.01).In our population, the NFKBIZ variant was an independent risk factor for developing early-onset CAD.

Perioperative neurocognition in elderly patients.

The extrinsic risk factors for postoperative cognitive disturbance have been a source of concern during the perioperative period, and these risk factors remain the subject of controversy. This review of recent studies focuses on the effect of these factors on postoperative cognitive disturbance during the perioperative period. Impairment of cerebral autoregulation may predispose patients to intraoperative cerebral malperfusion, which may subsequently induce postoperative cognitive disturbance. The neurotoxicity of several volatile anesthetics may contribute to cognitive functional decline, and the impact of intravenous anesthesia on cognitive function requires further exploration. Multimodal analgesia may not outperform traditional postoperative analgesia in preventing postoperative delirium. Furthermore, acute pain and chronic pain may exacerbate the cognitive functional decline of patients with preexisting cognitive impairment. The nuclear factor-kappa beta pathway is an important node in the neuroinflammatory network. Several intraoperative factors are associated with postoperative cognitive disturbance. However, if these factors are optimized in perioperative management, postoperative cognitive disturbance will improve.

Sulfasalazine treatment can cause a positive effect on LPS-induced endotoxic rats.

The aim of this study, was to determine the effect of sulfasalazine for different periods of time reduces disseminated intravascular coagulation, inflammation and organ damages by inhibiting the nuclear factor kappa beta pathway. The study was performed with 30 Wistar albino rats and the groups were established as Control group, LPS group; endotoxemia was induced with LPS, SL5 group: sulfasalazine (300 mg/kg, single dose daily) was administered for 5 days before the LPS-induced endotoxemia, and LS group: sulfasalazine (300 mg/kg, single dose) was administered similtenously with LPS. Hemogram, biochemical, cytokine (IL-1β, IL-6, IL-10, TNF-α) and acute phase proteins (HPT, SAA, PGE2) analyzes and oxidative status values were measured from blood samples at 3 and 6 h after the last applications in the all groups. The rats were euthanized at 6 h and mRNA levels of BCL2 and BAX genes were examined from liver and brain tissues. Sulfasalazine reduced the increased IL-1β, IL-6, TNF-α and PGE2 levels and significantly increased anti-inflammatory cytokine IL-10 levels. In addition, decreasing of ATIII level was prevented in the SL5 group, and decreasing of fibrinogen levels were prevented in the LS and SL5 groups within first 3 h. In LPS group, leukocyte and thrombocyte levels were decreased, however sulfasalazine application inhibited decreases of leukocyte levels in LS and SL5 groups. In addition, sulfasalazine inhibited the decrease of total antioxidant capacity and unchanged apoptosis in brain and liver. In conclusion, the use of sulfasalazine in different durations reduce the excessive inflammation of endotoxemia cases.

Triterpenoids principle of Wedelia calendulacea attenuated diethynitrosamine-induced hepatocellular carcinoma via down-regulating oxidative stress, inflammation and pathology via NF-kB pathway.

The aerial part of Wedelia calendulacea have been used in Ayurveda, Unani, Tibetan, Siddha and other folk medicine systems to protect the liver and renal tissue. Liver is considered as primary metabolizing site of body, which is prone to damage by endogenous and exogenous toxicants. A reason for liver toxicity, and major causes of the hepatocellular carcinoma (HCC). 19-α-Hydroxyurs-12(13)-ene-28 oic acid-3-O-β-D-glucopyranoside (HEG), a triterpenoids found in the higher plants, has been known to possess protective effect against various toxicants. The aim of the current study was to scrutinize the hepatoprotective mechanism of HEG against DEN-induced oxidative stress, hyperproliferation, inflammation and apoptosis tissue injury in Wistar rats. Invitro cell lines study of HEG scrutinized against the Hep-G2 and HuH-7 cells. A single dose of DEN (200mg/kg) and double dose of phenobarbitol were administered to induce the liver damage in rats; the dose treatment of HEG was terminated at the end of 22weeks. Macroscopical study was performed for the confirmation of hepatic nodules. The serum and hepatic samples were collected for further biochemical and histopathological analysis. Hepatic; non-hepatic; Phase I and II antioxidant enzymes were also examined. Additionally, we also scrutinized the inflammatory cytokines viz., tumor necrosis factor-α, interlukin-6, interlukin-1β, and Nuclear factor kappa beta (NF-kB), respectively. Histopathological study was also performed for analyzing the changes during the HCC. HEG confirmed the reduction of growth and deoxyribonucleic acid synthesis of both cell lines. DEN successfully induced the HCC in all group, which was significantly (p<0.001) altered by the HEG in a dose-dependent manner. The decreased level of pro-inflammatory cytokines and altered membrane-bound enzyme activity were also observed. HEG inhibits the phase I, II and antioxidant enzymes at the effective dose-dependent manner, which were considered as the precursor of the HCC. The alteration of phase I, II and antioxidant enzymes confirmed the inhibition of inflammatory reaction and oxidative stress, which directly or indirectly inhibited the NF-kB expression. Collectively, we can conclude that the HEG inhibited the growth of Hepatocellular carcinoma via attenuating the NF-kB pathway.

Targeting the Overexpressed YY1 in Cancer Inhibits EMT and Metastasis.

There have been recent developments in the treatment of various cancers, in particular non-metastatic cancers. However, many of the responding patients often relapse initially through the development of spread micro and macro-metastases. Unfortunately, there are very few therapeutic modalities for the treatment of metastatic cancers. The development of cancer metastasis has been proposed to involve the epithelial-mesenchymal transition (EMT), in which the tumor cells with the EMT phenotype exhibit various phenotypic markers and molecular modifications that are manifested to resist most conventional therapies. YY1 is a target of the hyperactivated nuclear factor-kappa beta pathway in cancer and it was reported that YY1 also regulates cell survival and cell proliferation in addition to its role in EMT and resistance. The overexpression of YY1 in the majority of cancers has been correlated with poor prognosis. It is hypothesized that targeting YY1 may result in several anti-tumor activities, including inhibition of cell survival and cell proliferation, inhibition of EMT, and reversal of resistance. This review discusses the potential therapeutic targeting of an overexpressed transcription factor, Yin Yang 1 (YY1), which has been implicated in the development of EMT and drug resistance. Several examples targeting YY1 in experimental models are presented.

Oral epithelial barrier function and the role of nuclear factor kappa-? pathway in the pathogenesis of aphthous ulceration

The normal oral mucosa is usually tolerant to its special microenvironment. Epithelial integrity and a wellmanaged immune system are important in sustaining harmony. A close look at the role played by adaptive immunity during recurrent aphthous ulcerations may throw some light into the pathogenesis. In this report, we provide a concise review of oral epithelial barrier function and present data on the possible pathogenetic mechanism of aphthous ulceration using immunohistocemical signs of nuclear factor kappa beta pathway activation on fourteen cases of mucosal aphthous ulcerations. We strongly support the hypothesis that oral aphthous ulcerations develop as a result of loss of epithelial barrier function and that nuclear factor kappa beta signaling pathway seems to be involved in this type of injury. Interventions that strengthen the mucosal barrier function or modulate inappropriate activation of nuclear factor kappa beta signaling pathway can be considered in the treatment of oral aphthous ulcerations.

Resveratrol prevents alcohol-induced cognitive deficits and brain damage by blocking inflammatory signaling and cell death cascade in neonatal rat brain

Human prenatal ethanol exposure that occurs during a period of increased synaptogenesis known as the 'brain growth spurt' has been associated with significant impairments in attention, learning and memory. Recent studies have shown that administration of ethanol to infant rats during the synaptogenesis period (first 2 weeks after birth) triggers extensive apoptotic neurodegeneration throughout many regions of the developing brain and results in cognitive dysfunctions as the animal matures. The present study was designed with an aim to investigate the effect of resveratrol, a polyphenolic phytoalexin (trans-3,5,4-trihydroxy stilbene) present in red wine on alcohol-induced cognitive deficits and neuronal apoptosis in rat pups postnatally exposed to ethanol. Pups were administered ethanol (5 g/kg, 12% v/v) by intragastric intubation on postnatal days 7, 8, and 9. Ethanol-exposed pups showed impaired memory performance in both Morris water maze elevated plus maze task recorded by using computer tracking with EthoVision software. Behavioral deficit in ethanol-exposed pups was associated with enhanced acetylcholinesterase activity, increased oxidative-nitrosative stress, cytokine (TNF-α, IL-1β and TGF-β), nuclear factor kappa beta and caspase 3 levels in both cerebral cortex and hippocampus. Chronic treatment with resveratrol (10 and 20 mg/kg) significantly attenuated all the behavioral, biochemical and molecular changes in different brain regions of ethanol administered pups. The major finding of the study is that resveratrol blocks activation of nuclear factor kappa beta pathway and apoptotic signaling and prevents cognitive deficits in rats postnatally exposed to ethanol.

Possible Genetic Dysregulation in Pediatric CFS

Hypocortisolism is a frequent finding in individuals with chronic fatigue syndrome (CFS) and could play an explanatory role in the development of illness symptomatology. The etiologic mechanism behind this finding could be genetic variance in glucocorticoid receptor expression (GR) or increased resistance to the effects of glucocorticoids. Several investigators believe that allelic variance in a GR (NR3C1) mediates the expression of chronic fatigue possibly through influence on hypothalamic-pituitary-adrenal (HPA) axis function [1]. In addition, several immunologic variables are associated with CFS. The nuclear factor kappa beta (NFkB) pathway is heavily involved in cellular transcription and regulation and has been shown to be associated with the development of CFS. The NFkB pathway is directly regulated by and influences the presence of GR [2]. Our study focused on assessing whether such inflammatory transcription is occurring during adolescent years. Findings indicated decreased expression of NFKB1, NFKB2, and NR3C1. A decrease in the expression of these genes may have effects on immune cell function and cytokine production that could explain immunologic findings seen in individuals with CFS.