Modulation Of Nuclear Factor Kappa Research Articles

N-acetylcysteine alleviates pulmonary alveolar proteinosis induced by indium-tin oxide nanoparticles in male rats: involvement of the NF-κB signaling pathway

Indium-tin oxide (ITO) was previously found to have a toxic effect on lung tissues, and oxidative stress and the inflammatory response are two important mechanisms of ITO‑induced lung injury. N-acetylcysteine (NAC) has been found to exhibit antioxidant and anti‑inflammatory properties. The current study aimed to evaluate the possible protective effects of NAC against ITO nanoparticle (Nano-ITO)-induced pulmonary alveolar proteinosis (PAP) in adult male Sprague-Dawley rats, especially via modulation of nuclear factor-kappa B (NF-κB) signaling. For this purpose, 50 rats were randomly allocated into five groups (10 rats each) as follows: (1) control group; (2) saline group; (3) NAC (200 mg/kg) group; (4) PAP model group receiving a repeated intratracheal dose of Nano-ITO (6 mg/kg); and (5) PAP model+NF-κB inhibitor (NAC) group pre-treated intraperitoneally with NAC (200 mg/kg) twice per week before the administration of an intratracheal dose of Nano-ITO (6 mg/kg). Rats were then euthanized under anesthesia, and their lungs were removed for histopathological and biochemical investigations. A 6 mg/kg dose of Nano-ITO markedly altered the levels of some oxidative stress biomarkers. The histological examination of Nano-ITO-exposed rats demonstrated diffused alveolar damage that involved PAP, cholesterol crystals, alveolar fibrosis, pulmonary fibrosis, and alveolar emphysema. The immunohistochemical results of Nano-ITO-exposed rats revealed strongly positive NF-κB p65 and inhibitory kappa B kinase (IKK)-β and weakly positive inhibitor of kappa-B subunit alpha (IκB-α) staining reactivity in the nuclei of cells lining the epithelium of the bronchioles and alveoli. Moreover, Nano-ITO activated the NF-κB pathway. However, pre-treatment with NAC significantly attenuated Nano-ITO-evoked alterations in the previously mentioned parameters, highlighting their antioxidant, anti-inflammatory, and anti-apoptotic potential. The results indicated that the degree of pulmonary fibrosis and proteinosis in the NAC‑treated group was improved compared with that in the Nano-ITO-induced PAP model group. The level of malondialdehyde was also decreased overall in the NAC-treated group compared with that in the Nano-ITO-induced model group, indicating that the pulmonary fibrosis degree and oxidation levels were decreased. The present study also demonstrated that NAC increased the activity of antioxidant enzyme superoxide dismutase and total antioxidant capacity, indicating that it could alleviate oxidative stress in the lung tissue of Nano-ITO‑exposed rats. In addition, NAC reduced the production of pro‑inflammatory cytokines interleukin (IL)‑1β, IL‑6, and tumor necrosis factor (TNF)‑α, and increased the levels of anti‑inflammatory factor IL‑10. The current study demonstrated that NAC can effectively attenuate Nano-ITO‑induced lung injury by reducing oxidative damage and the inflammatory response.

The action of phytochemicals present in cocoa in the prevention of vascular dysfunction and atherosclerosis

Chronic non-communicable diseases, including cardiovascular diseases (CVDs), have caused many deaths worldwide. Atherosclerotic plaque formation is common in individuals with CVDs. Thus, antioxidant and anti-inflammatory nutritional strategies can be used to prevent or inhibit this process. Due to its higher concentrations of cocoa, dark chocolate is considered a functional food due to the presence and action of phytochemical compounds, with anti-inflammatory and antioxidant actions. However, the recommended amounts of these compounds to prevent atherosclerosis have not yet been fully elucidated. The aim of the studywas to review the effects of cocoa and dark chocolate intake on the prevention of cardiovascular dysfunction and atherosclerosis. This narrative review was based on a search of PubMed and Lilacs. The search was conducted from September 2021 to February 2022 using the following keywords: flavonoids, cocoa, atherosclerosis, oxidative stress, and inflammation. The inclusion criteria were original articles, meta-analyses, and experimental and clinical studies published between 2002 and 2022 in English, focusing on the subject addressed. The exclusion criteria were the title and abstract reading and duplication of articles in the databases. The antioxidant and anti-inflammatory functions of phytochemicals in cocoa and dark chocolate are related to the modulation of nitric oxide through activation/phosphorylation and acting as a vasodilator. Furthermore, these phytochemicals reduce the formation of reactive oxygen species and activate antioxidant enzymes. The anti-inflammatory activities are related to the modulation of nuclear factor kappa B in the reduction of inflammatory markers, such as tumor necrosis factor-alpha, C-reactive protein, and pro-inflammatory cytokines, as well as in the reduction of adhesion molecules in the wall of the vases. The main phytochemicals present in cocoa and dark chocolates are catechins and their epicatechin isomers, which are responsible for improving inflammatory, metabolic, and antioxidant profiles. Its consumption can be encouraged, but with caution, owing to the caloric supply and forms of chocolate production, as these factors can reduce the presence of flavonoids in its composition. The antioxidant and anti-inflammatory functions of the phytochemicals in cocoa and dark chocolate are responsible for modulating nitric oxide via activation/phosphorylation and acting as a vasodilator. Reducing the formation of reactive oxygen species, as well as activating antioxidant enzymes. As for the anti-inflammatory activities, they modulate the nuclear factor kappa B, reducing inflammatory markers, thus improving the antioxidant and inflammatory profile of these patients.

Immunomodulatory effects of Inonotus obliquus polysaccharide on splenic lymphocytes infected with Toxoplasma gondii via NF-κB and MAPKs pathways

Context As a medicinal and edible fungus, Inonotus obliquus has been traditionally used to prevent and treat various ailments. Inonotus obliquus polysaccharide (IOP) isolated from I. obliquus processes many biological activities, our series of in vivo studies have shown that IOP protects against Toxoplasma gondii infection. Objective This study aimed to investigate the in vitro immunomodulatory effects and its mechanisms of IOP on mouse splenic lymphocytes infected with T. gondii. Materials and methods Mouse splenic lymphocytes were infected with T. gondii tachyzoites, and treated with different concentrations of IOP. The levels of cytokines and chemokines were measured by enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR). The expression of toll-like receptor 2 (TLR2) and TLR4, and the modulation of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) signaling pathways were determined by Western blot. Results IOP significantly decreased the over-release of cytokine interleukin-1 beta (IL-1β), IL-4, IL-6, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α) in supernatant from T. gondii-infected splenic lymphocytes. IOP also effectively inhibited the overexpression of cytokines and chemokine macrophage inflammatory protein-1 (MIP-1) and monocyte chemoattractant protein-1 (MCP-1) mRNA. Furthermore, IOP down-regulated TLR2 and TLR4 expressions and inhibited the over-phosphorylation of NF-κB p65 and inhibitor κBα (IκBα) in NF-κB signaling pathway and p38, c-Jun N-terminal kinase (JNK) in MAPKs signaling pathway. By observing the effect of IOP on TNF-α secretion after pretreatment with specific inhibitors, it was further confirmed that IOP was involved in the regulation of NF-κB, p38, and JNK signaling pathways. Conclusions These data indicate that IOP can inhibit the excessive inflammatory response caused by T. gondii infection through modulating NF-κB, p38, and JNK signaling pathways, and thus plays the in vitro anti-T. gondii role.

Sulforaphane as a Promising Natural Molecule for Cancer Prevention and Treatment.

Tumorigenicity-inhibiting compounds have been identified in our daily diet. For example, isothiocyanates (ITCs) found in cruciferous vegetables were reported to have potent cancer-prevention activities. The best characterized ITC is sulforaphane (SF). SF can simultaneously modulate multiple cellular targets involved in carcinogenesis, including (1) modulating carcinogen-metabolizing enzymes and blocking the action of mutagens; (2) inhibition of cell proliferation and induction of apoptosis; and (3) inhibition of neo-angiogenesis and metastasis. SF targets cancer stem cells through modulation of nuclear factor kappa B (NF-κB), Sonic hedgehog (SHH), epithelial-mesenchymal transition, and Wnt/β-catenin pathways. Conventional chemotherapy/SF combination was tested in several studies and resulted in favorable outcomes. With its favorable toxicological profile, SF is a promising agent in cancer prevention and/or therapy. In this article, we discuss the human metabolism of SF and its effects on cancer prevention, treatment, and targeting cancer stem cells, as well as providing a brief review of recent human clinical trials on SF.

Neuroprotective potential of fisetin in an experimental model of spinal cord injury: via modulation of NF-κB/IκBα pathway.

To evaluate neuroprotective efficacy of fisetin against the experimental model of spinal cord injury (SCI). SCI was induced in male Sprague-Dawley rats by placing an aneurysm clip extradurally. Rats were treated either with vehicle or fisetin for 28 days after SCI. Treatment with fisetin significantly attenuated SCI-induced alternations in mechano-tactile and thermal allodynia, hyperalgesia and nerve conduction velocities. SCI-induced upregulated tumor necrosis factor-alpha, interleukins, inducible nitric oxide synthase, cyclooxygenase-II, Bcl-2-associated X protein and caspase-3 mRNA expressions in the spinal cord and these were markedly reduced by fisetin. Spinal nuclear factor kappa B and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-alpha protein levels were also significantly downregulated by fisetin. Hematoxylin and eosin staining of spinal cord suggested that fisetin significantly ameliorated histological aberrations such as neuronal degeneration, necrosis and inflammatory infiltration induced in it. Fisetin exerts neuroprotection via modulation of nuclear factor kappa B/nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-alpha pathway by inhibiting release of inflammatory mediators (inducible nitric oxide synthase and cyclooxygenase-II), proinflammatory cytokines (tumor necrosis factor-alpha and interleukins), apoptotic mediators (Bcl-2-associated X protein and caspase-3).

TIPE2 Induced the Proliferation, Survival, and Migration of Lung Cancer Cells Through Modulation of Akt/mTOR/NF-κB Signaling Cascade.

Lung cancer represents the most common cause of cancer deaths in the world, constituting around 11.6% of all new cancer cases and 18.4% of cancer-related deaths. The propensity for early spread, lack of suitable biomarkers for early diagnosis, as well as prognosis and ineffective existing therapies, contribute to the poor survival rate of lung cancer. Therefore, there is an urgent need to develop novel biomarkers for early diagnosis and prognosis which in turn can facilitate newer therapeutic avenues for the management of this aggressive neoplasm. TIPE2 (tumor necrosis factor-α-induced protein 8-like 2), a recently identified cytoplasmic protein, possesses enormous potential in this regard. Immunohistochemical analysis showed that TIPE2 was significantly upregulated in different stages and grades of lung cancer tissues compared to normal lung tissues, implying its involvement in the positive regulation of lung cancer. Further, knockout of TIPE2 resulted in significantly reduced proliferation, survival, and migration of human lung cancer cells through modulation of the Akt/mTOR/NF-κB signaling axis. In addition, knockout of TIPE2 also caused arrest in the S phase of the cell cycle of lung cancer cells. As tobacco is the most predominant risk factor for lung cancer, we therefore evaluated the effect of TIPE2 in tobacco-mediated lung carcinogenesis as well. Our results showed that TIPE2 was involved in nicotine-, nicotine-derived nitrosamine ketone (NNK)-, N-nitrosonornicotine (NNN)-, and benzo[a]pyrene (BaP)-mediated lung cancer through inhibited proliferation, survival, and migration via modulation of nuclear factor kappa B (NF-κB)- and NF-κB-regulated gene products, which are involved in the regulation of diverse processes in lung cancer cells. Taken together, TIPE2 possesses an important role in the development and progression of lung cancer, particularly in tobacco-promoted lung cancer, and hence, specific targeting of it holds an enormous prospect in newer therapeutic interventions in lung cancer. However, these findings need to be validated in the in vivo and clinical settings to fully establish the diagnostic and prognostic importance of TIPE2 against lung cancer.

Antioxidant and Anti-Inflammatory Activities of Flavanones from Glycyrrhiza glabra L. (licorice) Leaf Phytocomplexes: Identification of Licoflavanone as a Modulator of NF-kB/MAPK Pathway.

Inflammation represents an adaptive response generated by injuries or harmful stimuli. Natural remedies represent an interesting alternative to traditional therapies, involving several biochemical pathways. Besides, the valorization of agrochemical wastes nowadays seems to be a feasible way to reduce the health spending and improve the accessibility at bioactive natural compounds. In this context, the chemical composition of three Glycyrrhiza glabra L. (licorice) leaf extracts, obtained through maceration or ultrasound-assisted method (fresh and dried leaves) was investigated. A guided fractionation obtained three main components: pinocembrin, glabranin and licoflavanone. All the extracts showed similar antioxidant properties, evaluated by 2,2′-diphenyl-1-picrylhydrazyl (DPPH) or 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) Diammonium Salt (ABTS) assay, while, among the isolated compounds, licoflavanone exhibited the best antioxidant activity. The anti-inflammatory activity of the extracts and the purified compounds was investigated in lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophages. Extract C and licoflavanone showed a good anti-inflammatory activity without affecting cell viability, as they decreased nitrite levels even when used at 12.5 μg/mL (p < 0.005) and 50 μM concentration (p < 0.001), respectively. Interestingly, licoflavanone markedly decreased pro-inflammatory cytokines and cyclooxygenase 2/inducible nitric oxide synthase (COX-2/iNOS) expression levels (p < 0.001). A modulation of nuclear factor kappa B/mitogen-activated protein kinases (NF-kB/MAPK) pathway underlay such behavior, highlighting the potential of this natural compound as a new scaffold in anti-inflammatory drug research.

The Use of Azoles Containing Natural Products in Cancer Prevention and Treatment: An Overview.

Cancer is one of the leading causes of death worldwide. In view of ever increasing number associated with cancer related death, there is an urgent need to find out a novel compound especially of natural origin (better efficacy, less or non-toxic and cost effective) that could serve against the treatment of all forms of cancer. Currently, available treatment options related to cancer have their certain limitations especially in the case of solid tumors. In search of the natural anticancer compound, alkaloids, in general, have been exploited by the scientist working in this field of research. Among these alkaloids, azoles (secondary metabolite) have been significantly highlighted in literature because of their anticancer potential and better efficacy against various forms of cancer. Their mechanism of action includes induction in the cleavage of poly-ADP ribose polymerase (PARP), induction of caspase 3 and caspase 9, modulation of nuclear factor kappa B, damage to DNA, cell cycle arrest at G1 and G2/M stage, apoptosis and c-Myb inhibition. In the current article, we have tried to cover various azoles especially from oxazoles, thiazoles and carbazoles class that have been reported for their anticancer potential. Based on our article, we believe that, soon, the scientific community will come up with certain azole which will work against cancer at large rather than a specific type of cancer.

Modulation of nuclear factor-kappa B activation by the endoplasmic reticulum stress sensor PERK to mediate estrogen-induced apoptosis in breast cancer cells

Stress responses are critical for estrogen (E2)-induced apoptosis in E2-deprived breast cancer cells. Nuclear factor-kappa B (NF-κB) is an important therapeutic target to prevent stress responses in chronic inflammatory diseases including cancer. However, whether E2 activates NF-κB to participate in stress-associated apoptosis in E2-deprived breast cancer cells is unknown. Here, we demonstrated that E2 differentially modulates NF-κB activity according to treatment time. E2 initially has significant potential to suppress NF-κB activation; it completely blocks tumor necrosis factor alpha (TNFα)-induced activation of NF-κB. We found that E2 preferentially and constantly enhances the expression of the adipogenic transcription factor CCAAT/enhancer binding protein beta (C/EBPβ), which is responsible for the suppression of NF-κB activation by E2 in MCF-7:5C cells. Interestingly, NF-κB p65 DNA-binding activity is increased when E2 is administered for 48 h, leading to the induction of TNFα and associated apoptosis. Blocking the nuclear translocation of NF-κB can completely prevent the induction of TNFα and apoptosis induced by E2. Further examination revealed that protein kinase RNA-like endoplasmic reticulum kinase (PERK), a stress sensor of unfolded protein response (UPR), plays an essential role in the late activation of NF-κB by E2. This modulation between PERK and NF-κB is mainly mediated by a stress responsive transcription factor, transducer and activator of transcription 3 (STAT3), independently of the classic canonical IκBα signaling pathway. Thus, inhibition of PERK kinase activity completely blocks the DNA binding of both STAT3 and NF-κB, thereby preventing induction of NF-κB-dependent genes and E2-induced apoptosis. All of these findings suggest that PERK is a key regulator to convey stress signals from the endoplasmic reticulum to the nucleus and illustrate a crucial role for the novel PERK/STAT3/NF-κB/TNFα axis in E2-induced apoptosis in E2-deprived breast cancer cells.

Umbelliferon-α-d-glucopyranosyl-(2I → 1II)-α-Dglucopyranoside ameliorates Diethylnitrosamine induced precancerous lesion development in liver via regulation of inflammation, hyperproliferation and antioxidant at pre-clinical stage

It is well documented that anomalous production of inflammatory proteins linked with most of the toxic expression and genesis of diverse chronic disease including cancer. Diethylnitrosamine (DEN) a well-known hepatotoxin and hepatocarcinogen, can induce oxidative stress and inflammatory reaction in it. Umbelliferone, secondary metabolites, is present in different plants and widely consumed by humans as medicine and food supplements. The aim of the current study was to scrutinize the chemoprotective potential of umbelliferon-α-d-glucopyranosyl-(2I→1II)-α-d-glucopyranoside (UFD) against DEN-induced hepatocellular carcinoma (HCC) in experimental rats. Single intraperitoneal injection of DEN (200mg/kg) was used for induction of HCC in rats and rats were grouped and orally treated with UFD (5, 10 and 20mg/kg) dose for 22 weeks. Parameters under investigation included hepatic, non-hepatic enzymes, oxidative stress, pro-inflammatory cytokines, COX-2 and NF-κB level along with histopathological examination in HCC rats. UFD exerted protective effect via reduction of oxidative stress, liver and non-liver parameters in a dose-dependent manner. It also reduced the expression of TNF-α, IL-1β, IL-6 and COX-2 in diseased rats. Our result revealed the essential repression of the inflammation cascade through modulation of nuclear factor-kappa B (NF-κB) signaling pathway.

Abstract 2332: Integral modulation of nuclear factor-kappa B activation by C/EBPβ and the endoplasmic reticulum stress sensor PERK to mediate estrogen-induced apoptosis in estrogen-deprived breast cancer cells

Abstract Stress responses are critical for estrogen (E2) to induce apoptosis in E2-deprived breast cancer cells. Nuclear factor-kappa B (NF-κB) is well known as a therapeutic target to prevent stress responses in chronic inflammatory diseases including cancer. However, whether E2 activates NF-κB to participate in stress-associated apoptosis in E2-deprived breast cancer cells is unclear. We demonstrated that E2 differentially modulates NF-κB activity in E2-deprived breast cancer cells according to the treatment time. Because E2 initially has significant potential to down modulate the NF-κB activation, it completely suppresses the tumor necrosis factor alpha (TNFα)-induced NF-κB activation. We found that E2 preferentially and constantly enhances the expression of transcription factor CCAAT/enhancer binding protein beta (C/EBPβ) which is responsible for suppression of NF-κB activation by E2 in MCF-7:5C cells. The mTOR signaling pathway promotes repression of NF-κB by C/EBPβ which is confirmed by the evidence that inhibition of mTOR is synergistic with E2 to upregulate NF-κB-dependent genes, such as TNFα. Interestingly, NF-κB p65 activity is upregulated when E2-treatment is administered for 48 hours, leading to induction of TNFα. Blocking the nuclear translocation of NF-κB completely prevents E2 from induction of TNFα and apoptosis. Importantly, protein kinase RNA-like endoplasmic reticulum kinase (PERK), a stress sensor of unfolded protein response, is activated by E2 and plays an essential role in increasing NF-κB p65 DNA binding through the activation of STAT3, independently of canonical IκBα signal pathway. Thus, inhibition of PERK kinase activity completely blocks nuclear activation of NF-κB and NF-κB-dependent induction of TNFα, thereby preventing E2-induced apoptosis. All of these findings illustrate a crucial role for the novel PERK/NF-κB/TNFα axis in E2-induced apoptosis which is integrally modulated by the stress responsive transcription factor C/EBPβ and endoplasmic reticulum stress. This study provides an important rationale for exercising caution in clinical trials when considering targeting PERK or NF-κB following the development of acquired resistance to aromatase inhibitors whereas mTOR may be a target to enhance the therapeutic effects of E2 in antihormone resistant breast cancer. Citation Format: Ping Fan, Amit K. Tyagi, Fadeke A. Agboke, Niranjana Pokharel, V. Craig Jordan. Integral modulation of nuclear factor-kappa B activation by C/EBPβ and the endoplasmic reticulum stress sensor PERK to mediate estrogen-induced apoptosis in estrogen-deprived breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2332. doi:10.1158/1538-7445.AM2017-2332

Genetic and epigenetic cancer chemoprevention on molecular targets during multistage carcinogenesis.

The main goal of cancer chemoprevention is to prevent or halt the progression of carcinogenesis with the administration of synthetic or natural compounds. Fundamental chemopreventive strategies include inhibition of genetic damage, anti-proliferation/cell cycle regulation, and induction of apoptosis and anti-inflammatory processes, which may be critical for carcinogenesis intervention. Recently, a new paradigm for identifying chemopreventive agents has been implemented. It focuses on defining new biomarkers that can be used to evaluate chemopreventive efficacy based on multistage carcinogenesis. The functional roles of chemopreventive agents are associated with the modulation of nuclear factor kappa B, nuclear factor erythroid 2-related factor, p53, AMPK/mTOR, phosphatidylinositol 3-kinase, epidermal growth factor receptor, cyclooxygenase-2, chemokine (C-X-C motif) receptor 2, and sphingosine-1-phosphate. This paper summarizes the genetic and epigenetic effects of chemopreventive agents on the expression of cancer-related target genes mediated by epigenetic alterations, such as DNA methylation and histone modifications. This review will provide unique and effective strategies for reducing cancer and aging-related diseases in humans.

Studies on the Antidiabetic and Antinephritic Activities of Paecilomyces hepiali Water Extract in Diet-Streptozotocin-Induced Diabetic Sprague Dawley Rats.

Paecilomyces hepiali is a fungus widely used in Asian countries for various potential pharmacological activities. The present study aims to evaluate the antidiabetic and antinephritic effects of the Paecilomyces hepiali mycelium water extract (PHC) in diabetic rat, which is established by eight-week high-fat diet administration followed by one-week tail intravenous injection of 25 mg/kg streptozotocin (STZ). After four-week 0.12 g/kg metformin and PHC at doses of 0.08, 0.4, and 2.0 g/kg treatment, an increment of body weight, a decrement of plasma glucose, low levels of total cholesterol, and low density lipoprotein cholesterol in diabetic rats were observed. PHC promotes glucose metabolism by enhancing insulin, pyruvate kinase activity, and increasing the synthesis of glycogen. PHC normalized the disturbed levels of superoxide dismutase, methane dicarboxylic aldehyde, and glutathione peroxidase in kidney. The inhibitory effects on the levels of interleukin-2, interleukin-6, interleukin-10, and tumor necrosis factor-α in serum and kidney revealed the protection of PHC against diabetic nephropathy. Compared with nontreated diabetic rats, four-week PHC treatment resulted in a decrement on nuclear factor kappa B expression in kidney. These results show that Paecilomyces hepiali possesses antidiabetic and antinephritic effects which are related to the modulation of nuclear factor kappa B activity.

Stimulation of the α7 nicotinic acetylcholine receptor protects against neuroinflammation after tibia fracture and endotoxemia in mice.

Surgery and critical illness often associate with cognitive decline. Surgical trauma or infection can lead independently to learning and memory impairments via similar, but not identical, cellular signaling of the innate immune system that promotes neuroinflammation. In this study we explored the putative synergism between aseptic orthopedic surgery and infection, the latter reproduced by postoperative lipopolysaccharide (LPS) administration. We observed that surgery and LPS augmented systemic inflammation up to postoperative d 3 and this was associated with further neuroinflammation (CD11b and CD68 immunoreactivity) in the hippocampus in mice compared with those receiving surgery or LPS alone. Administration of a selective α7 subtype nicotinic acetylcholine receptor (α7 nAChR) agonist 2 h after LPS significantly improved neuroinflammation and hippocampal-dependent memory dysfunction. Modulation of nuclear factor-kappa B (NF-κB) activation in monocytes and regulation of the oxidative stress response through nicotinamide adenine dinucleotide phosphate (NADPH) signaling appear to be key targets in modulating this response. Overall, these results suggest that it may be conceivable to limit and possibly prevent postoperative complications, including cognitive decline and/or infections, through stimulation of the cholinergic antiinflammatory pathway.

Role of α-lipoic acid in dextran sulfate sodium-induced ulcerative colitis in mice: Studies on inflammation, oxidative stress, DNA damage and fibrosis

Ulcerative colitis affects many people worldwide. Inflammation and oxidative stress play a vital role in its pathogenesis. Previously, we reported that ulcerative colitis leads to systemic genotoxicity in mice. The present study was aimed at elucidating the role of α-lipoic acid in ulcerative colitis-associated local and systemic damage in mice. Experimental colitis was induced using 3%w/v dextran sulfate sodium in drinking water for 2 cycles. α-Lipoic acid was administered in a co-treatment (20, 40, 80 mg/kg bw) and post-treatment (80 mg/kg bw) schedule. Various biochemical parameters, histological evaluation, comet and micronucleus assays, immunohistochemistry and western blot analysis were employed to evaluate the effect of α-lipoic acid in mice with ulcerative colitis. The protective effect of α-lipoic acid was mediated through the modulation of nuclear factor kappa B, cyclooxygenase-2, interleukin 17, signal transducer and activator of transcription 3, nuclear erythroid 2-related factor 2, NADPH: quinone oxidoreductase-1, matrix metalloproteinase-9 and connective tissue growth factor. Further, ulcerative colitis led to an increased gut permeability, plasma lipopolysaccharide level, systemic inflammation and genotoxicity in mice, which was reduced with α-lipoic acid treatment. The present study identifies the underlying mechanisms involved in α-lipoic acid-mediated protection against ulcerative colitis and the associated systemic damage in mice.

Differential regulation of nuclear factor-kappa B subunits on epidermal keratinocytes by ultraviolet B and tacrolimus

Modulation of nuclear factor-kappa B (NF-κB) expression has important clinical implications including anti-inflammation. Recently, we have shown that direct regulation of NF-κB/p65 subunit may account for tacrolimus ointment’s remarkable clinical efficacy on treating inflammatory dermatoses. However, NF-κB is a dimeric transcription factor formed by hetero- or homodimeration of the five Rel family proteins. The complete operational scheme of different NF-κB subunits remains obscure. It has been shown that homodimers consist of NF-κB/p50 may serve an inhibitory role in suppressing inflammation while dimers consisting of NF-κB/p65 activate inflammatory pathway. Our current study aimed to explore the effects of ultraviolet B (UVB) on epidermal keratinocytes in terms of specific NF-κB subunits NF-κB/p50 and NF-κB/p65. Additionally, the effects of tacrolimus on differential regulation of NF-κB subunits of UVB irradiated keratinocytes were also investigated. Our result showed that UVB sequentially regulated the activities of different subunits of NF-κB: the activity of NF-κB/p50 was downregulated in the early stage (6 hours), followed by upregulation of NF-κB/p65 in the later stage (12 hours). The results from immunofluorescence, immunocytochemical, and immunohistochemical analyses indicated that the nuclear expression of NF-κB/p50 could be seen constitutively while the nuclear expression of NF-κB/p65 could only be seen after UVB irradiation. Furthermore, treatment with tacrolimus didn’t affect the nuclear activation and translocation of NF-κB/p50, while the UVB induced NF-κB/p65 nuclear expression was suppressed by tacrolimus. In summary, we have shown that UVB irradiation sequentially regulated different NF-κB subunits. The clinical efficacy of tacrolimus may be attributed to its specific regulatory effect on NF-κB/p65 but not NF-κB/p50 of the NF-κB pathway.

Ibudilast, a Pharmacologic Phosphodiesterase Inhibitor, Prevents Human Immunodeficiency Virus-1 Tat-Mediated Activation of Microglial Cells

Human Immunodeficiency Virus-1 (HIV-1)-associated neurocognitive disorders (HAND) occur, in part, due to the inflammatory response to viral proteins, such as the HIV-1 transactivator of transcription (Tat), in the central nervous system (CNS). Given the need for novel adjunctive therapies for HAND, we hypothesized that ibudilast would inhibit Tat-induced excess production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNFα) in microglial cells. Ibudilast is a non-selective cyclic AMP phosphodiesterase inhibitor that has recently shown promise as a treatment for neuropathic pain via its ability to attenuate glial cell activation. Accordingly, here we demonstrate that pre-treatment of both human and mouse microglial cells with increasing doses of ibudilast inhibited Tat-induced synthesis of TNFα by microglial cells in a manner dependent on serine/threonine protein phosphatase activity. Ibudilast had no effect on Tat-induced p38 MAP kinase activation, and blockade of adenosine A2A receptor activation did not reverse ibudilast's inhibition of Tat-induced TNFα production. Interestingly, ibudilast reduced Tat-mediated transcription of TNFα, via modulation of nuclear factor-kappa B (NF-κB) signaling, as shown by transcriptional activity of NF-κB and analysis of inhibitor of kappa B alpha (IκBα) stability. Together, our findings shed light on the mechanism of ibudilast's inhibition of Tat-induced TNFα production in microglial cells and may implicate ibudilast as a potential novel adjunctive therapy for the management of HAND.

Probiotic supplementation: an alternative in the treatment of mycosis fungoides?

Editor The current treatment strategies for patients with mycosis fungoides and Sézary syndrome had been published in the EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome.1 In the early stages of cutaneous T-cell lymphoma (CTCL; mycosis fungoides, stages IA, IB and IIA), skin-directed therapies like topical corticosteroids, BCNU (carmustine), nitrogen mustard, bexarotene gel or systemic psoralen plus ultraviolet A (PUVA) phototherapy, UVB broad- or narrow-band phototherapy, localized radiotherapy or total skin electron beam therapy are recommended for first-line treatment. Here, we report a case of early-stage annular mycosis fungoides. A 38-year-old woman had been diagnosed with annular mycosis fungoides at the age of 19. Previous therapy included X-ray radiation (Dermopan) of the left flank and intermittent local corticosteroids. For 17 months, she received low-dose interferon alpha-2a, 6 million IU subcutaneously three times per week in combination with PUVA therapy, resulting in a complete response for 1 year. A flare-up was noticed around the irradiated skin area on the left flank. A 15 × 20 cm polycyclic annular erythematous plaque with fine scaling was seen (Fig. 1). The local treatment with corticosteroids had no benefit and the lesion grew larger centrifugally. A skin re-biopsy of the erythematous annular plaque was done. The biopsy showed a dense infiltrate of atypical lymphocytes, some forming groups within the epidermis (Pautrier micoabscesses) with a CD3+, CD4+ phenotype. The TCR-γ-PCR GeneScan analysis of the tissue showed a monoclonal T-cell population. The diagnosis of mycosis fungoides was confirmed. A 15 × 20 cm polycyclic annular erythematous plaque with fine scaling surrounding an area of post-irradiation hypo- and hyperpigmentation on the left flank. We discussed the therapeutic options such as localized PUVA therapy and systemic treatment with bexarotene with the patient. Radiotherapy was not recommended due to previous irradiation therapy leading to scaring. The patient preferred a wait-and-see strategy and refused the offered treatment options. At the same time, she started probiotic supplementation with Lactobacillus gasseri (8 × 108 to 8 × 109 KBE/g) and Bifidobacterium longum (8 × 108 to 8 × 109 KBE/g) daily for the prevention of intestinal infection. Probiotic supplements are generally well tolerated because the contained microorganisms are identical to those found in the human gastrointestinal tract. Interestingly, after 8 weeks of treatment with probiotic supplementation, the annular plaques changed colour to reddish-brown, and after 6 months, the lesions were almost gone (Fig. 2). The patient reported that she was not using any other ointment or therapy to treat the mycosis fungoides skin lesion. It could be speculated whether the complete regression of the annular mycosis fungoides skin lesion was induced by probiotic supplementation. However, clinical regression of annular mycosis fungoides lesions without therapy2 and a complete regression of CTCL, unspecified after skin biopsy, were described.3 Complete clearance of the mycosis fungoides lesion on the left flank after 6 months treatment with probiotic supplementation; only the irradiated skin was seen. Recent clinical trials have evaluated the clinical effectiveness of probiotics in the treatment and prevention of a wide range of acute and chronic gastrointestinal diseases,4,5 such as infectious diarrhoea, antibiotic associated diarrhoea, irritable bowel syndrome, inflammatory bowel disease and Helicobacter pylori infection. Several studies have also evaluated their efficacy in reducing the incidence of atopic clinical symptoms with promising results6 and other non-gastrointestinal diseases, such as respiratory infections, urogenital tract infections vaginitis and hypercholesterolaemia.5 There are various randomized studies and reports in the literature for the recommendation of probiotic supplementation in cancer prevention, particularly in colon,7 bladder, breast8 and liver cancer. Nevertheless, the clinical evidence for probiotic use in cancer prevention is insufficient. However, no successful treatment of cancer was reported. A recent study investigated the molecular mechanisms of pro-apoptotic effects of the probiotic Lactobacillus reuteri.9 They showed that L. reuteri promotes tumour necrosis factor–induced apoptosis in human myeloid leukaemia-derived cells by modulation of nuclear factor-kappa B (NK-kappaB) and mitogen-activated protein kinase signalling. This could be a possible explanation for the observed clinical effect because CTCL tumour cells are resistant to apoptosis by various mechanisms including constitutive activation of NF-kappaB.10 This might be the target of the probiotic bacteria in the tumour cells of our patient. However, it remains an open question if probiotics are able to induce apoptosis in CTCL tumour cells, and if sufficient dosages might reach the CTCL tumour cells in the skin. In conclusion, we present a patient with mycosis fungoides in whom probiotic supplementation may have lead to clearance of mycosis fungoides skin lesions.

NF-κB inhibition is involved in tobacco smoke-induced apoptosis in the lungs of rats

Apoptosis is a vital mechanism for the regulation of cell turnover and plays a critical role in tissue homeostasis and development of many disease processes. Previous studies have demonstrated the apoptotic effect of tobacco smoke; however, the molecular mechanisms by which tobacco smoke triggers apoptosis remain unclear. In the present study we investigated the effects of tobacco smoke on the induction of apoptosis in the lungs of rats and modulation of nuclear factor-kappa B (NF-κB) in this process. Exposure of rats to 80 mg/m 3 tobacco smoke significantly induced apoptosis in the lungs. Tobacco smoke resulted in inhibition of NF-κB activity, noted by suppression of inhibitor of κB (IκB) kinase (IKK), accumulation of IκBα, decrease of NF-κB DNA binding activity, and downregulation of NF-κB-dependent anti-apoptotic proteins, including Bcl-2, Bcl-xl, and inhibitors of apoptosis. Initiator caspases for the death receptor pathway (caspase 8) and the mitochondrial pathway (caspase 9) as well as effector caspase 3 were activated following tobacco smoke exposure. Tobacco smoke exposure did not alter the levels of p53 and Bax proteins. These findings suggest the role of NF-κB pathway in tobacco smoke-induced apoptosis.

Pentoxifylline Decreases Up-Regulated Nuclear Factor kappa B Activation and Cytokine Production in the Rat Retina following Transient Ischemia

Aim: To investigate whether pentoxifylline (PTX) could influence the increased cytokine gene expression in the retina flowing transient ischemia, and if so, whether it acts through the modulation of nuclear factor kappa B (NF-ĸB) activation. Methods: Sprague-Dawley rats were randomly divided into three equal groups: control group, saline-treated group, and PTX-treated group. Increased intraocular pressure was applied for 90 min to induce retinal ischemia, and reperfusion was established by lowering the bottle to eye level. The reperfusion period lasted for 48 h. In the PTX-treated group, an initial dose of 20 mg PTX was injected via tail vein at the beginning of reperfusion. Then the rat received infusion of PTX at a rate of 6 mg/kg/h throughout the entire reperfusion period. The retinal tissues were collected at the end of 1, 6, 12, 24, and 48 h of reperfusion, respectively, for biochemical analysis. Histological examination was done on the tissues collected at the end of 48 h after reperfusion. Results: Histological examination revealed reduction of overall retinal thickness and thinning of the inner retinal layer in saline-treated rats after 48-hour reperfusion. However, PTX treatment significantly reduced the loss of overall retinal thickness and thinning of inner retinal layers. Dramatic increase in NF-ĸB activation, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) production and mRNA expression were observed in the saline-treated group after reperfusion, with the peak reached around 12 h. In the PTX-treated group, NF-ĸB activation, TNF-α and IL-1β production and mRNA expression were significantly reduced at each corresponding time point compared to the saline-treated group. Conclusion: PTX decreased the up-regulated activation of NF-ĸB and the expression of proinflammatory cytokines, TNF-α and IL-1β in rat retinas following ischemia/reperfusion. This may contribute to significantly reduce the loss of overall retinal thickness and thinning of inner retinal layers.