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Increased Proinflammatory Cytokine Production by Chronic Hepatitis B Patients with Mutant Hepatitis B Virus: Plausible Mechanisms Underlying Severe Liver Diseases in These Patients

Raihan R, Akbar SMF, Al Mahtab M, Khan MSI, Tabassum S, Tee KK, et al.

Viral Immunol, 2020 09;33(7):530-534.
PMID: 32513066 DOI: 10.1089/vim.2019.0198

Hepatitis B virus (HBV) is a noncytopathic virus and billions of HBV-infected patients live uneventful lives and do not suffer from notable liver damage. However, HBV also causes progressive liver diseases characterized by hepatic inflammation, hepatic fibrosis, and liver cancer in millions of HBV-infected patients. The goal of this study was to evaluate the role of mutant HBV in HBV pathogenesis. In a cohort of 360 chronic HBV-infected patients, mutations at T1762/A1764 of HBV genome were detected in most of the patients with HBV-induced liver cirrhosis and hepatocellular carcinoma. To explore if mutations at T1762/A1764 of HBV genome has any role in progressive liver disease, peripheral blood mononuclear cells (PBMCs) and antigen-presenting dendritic cells (DCs) were isolated from five chronic hepatitis B (CHB) patients with mutations at T1762/A1764 and five comparable patients of CHB without mutations at T1762/A1764. DCs were pulsed with hepatitis B surface antigen (HBsAg). The levels of cytokines produced by PBMCs and DCs as well as nitrite production by DCs were evaluated. Significantly higher levels of interleukin-12, tumor necrosis factor-alpha, interferon-gamma, and transforming growth factor-beta were detected in cultures of PBMCs, DCs, and HBsAg-pulsed DCs from CHB patients with mutations at T1762/A1764 compared with those without mutations (p

Matched MeSH terms: Tumor Necrosis Factor-alpha/metabolism
Therapeutic efficacy of seaweed extract (Ulva Fasciata Delile) against invasive candidiasis in mice

Fathy SA, Mohamed MR, Emam MA, Mohamed SS, Ghareeb DA, Elgohary SA, et al.

Trop Biomed, 2019 Dec 01;36(4):972-986.
PMID: 33597467

Candida is the most frequent common causes of invasive fungal infections and associated with high morbidity and mortality. Most of available antifungal agents have side effects. This opened up new avenues to investigate the antifungal efficacy of active extracts from marine algae. So the aim of this study was to evaluate the protective and the curative effect of Ulva fasciata extract against an invasive candidiasis in mice and to study its underlying mechanism. The active ingredients of Ulva fasciata extract were evaluated using HPLC and GC/MS. Fifty mice were included in current work, and the level of inflammatory markers; Interleukin (IL)-4, IL-12, Interferon-gamma (IFN-γ) and Tumor necrosis factor-alpha (TNF-α) were determined using ELISA kits. Hematological, biochemical and oxidative stress parameters were determined using commercial kits. Moreover, the histopathological examinations were carried on liver, kidney and spleen for all groups. The results obtained showed that treatment with U. fasciata either before or after Candida infection significantly improved the hematological, biochemical alterations and antioxidant status caused by this infection. Furthermore, the U. fasciata reduced histopathological changes induced by Candida as well as it could increase the expression of IL-12 and IFN-γ while minimized the expression of TNF-α and IL-4 in all infected mice compared to infected untreated mice. These data propose that U. fasciata can ameliorate inflammatory reactions related to Candida albicans cytotoxicity via its ability to augment cellular antioxidant defenses by its active compounds.

Matched MeSH terms: Tumor Necrosis Factor-alpha/metabolism
Fulltext The Efficacy of Processing Strategies on the Gastroprotective Potentiality of Chenopodium quinoa Seeds

Mariod AA, Salama SM

ScientificWorldJournal, 2020;2020:6326452.
PMID: 32549800 DOI: 10.1155/2020/6326452

The current study has been conducted to evaluate the effect of different processing techniques on the 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging capacity and the gastroprotective potential of Chenopodium quinoa red seeds in acute gastric injury induced by absolute ethanol in rats. Seven groups of female Sprague Dawley rats were assigned to normal and absolute ethanol (absolute EtOH) groups, given distilled water, reference control omeprazole (OMP, 20 mg/kg), pressure-cooked quinoa seeds (QP, 200 mg/kg), first stage-germinated quinoa seeds (QG, 200 mg/kg), Lactobacillus plantarum bacteria-fermented quinoa seeds (QB, 200 mg/kg), and Rhizopus oligosporus fungus-fermented quinoa seeds (QF, 200 mg/kg). One hour after treatment, all groups were given absolute ethanol, except for the normal control rats. All animals were sacrificed after an additional hour, and the stomach tissues were examined for histopathology of hematoxylin and eosin staining, immunohistochemistry of cyclooxygenase 2 (COX-2), and nitric oxide synthase (iNOS). Stomach homogenates were evaluated for oxidative stress parameters and prostaglandin E2 (PGE2). Gene expression was performed for gastric tumor necrosis factor alpha (TNF-α) and nuclear factor kappa of B cells (NF-kB). QB and QG recorded the highest DPPH scavengers compared to QF and QP. The gastroprotective potential of QB was comparable to that of OMP, followed by QF, then QG, and QP as confirmed by the histopathology, immunohistochemistry, and gene expression assessments. In conclusion, differently processed red quinoa seeds revealed variable antioxidant capacity and gastroprotective potential, while the bacterial fermented seeds (QB) showed the highest potential compared to the other processing techniques. These results might offer promising new therapy in the treatment of acute gastric injury.

Matched MeSH terms: Tumor Necrosis Factor-alpha/metabolism
Fulltext The Cytokine and Bone Protein Expression by Ellagic Acid-Hydroxyapatite in Bone Remodelling Model

Primasari DN, Nirwana I, Budi HS, Wardhana AS, Sari AF, Novita N, et al.

ScientificWorldJournal, 2022;2022:6740853.
PMID: 36561943 DOI: 10.1155/2022/6740853

OBJECTIVE: Ellagic acid, a phenolic compound with anti-inflammatory potential, can be used to accelerate the bone healing process and affect human health, while hydroxyapatite is the most commonly used bone graft material. Using a combination of the two materials results in reduced inflammation and increased osteogenesis. This study aimed to determine the effects of combining ellagic acid and hydroxyapatite in bone marker remodelling by analysing the expression of tumour necrosis factor-α (TNF-α), interleukin 10 (IL-10), bone morphogenetic 4 protein (BMP-4), and osteopontin (OPN).
METHODS: Thirty Wistar rats were used in the study. A defect was created in each animal's femur using a low-speed diamond bur. In the control group, the bone was then treated with polyethylene glycol (PEG). In one of the other groups, the bone was treated with hydroxyapatite, and in the other, with ellagic acid-hydroxyapatite. The femur was biopsied 7 days after the procedure and again 14 days after the procedure, and an indirect immunohistochemical (IHC) examination was performed for TNF-α, IL-10, BMP-4, and OPN expression.
RESULTS: The ellagic acid-hydroxyapatite decreased TNF-α expression in the bone tissue after 7 days and again after 14 days (p

Matched MeSH terms: Tumor Necrosis Factor-alpha/metabolism
The oxidative stress of hyperglycemia and the inflammatory process in endothelial cells

Muniandy S, Qvist R, Yan GO, Bee CJ, Chu YK, Rayappan AV

J. Med. Invest., 2009 Feb;56(1-2):6-10.
PMID: 19262007

Hyperglycemia and insulin resistance are common in many critically ill patients. Hyperglycemia increases the production of reactive oxygen species in cells, stimulates the production of the potent proinflammatory cytokines IL-8 and TNF-alpha, and enhances the expression of haem oxygenase-1, an inducible stress protein. It has been shown that administration of insulin and the semi-essential amino acid glutamine have been beneficial to the septic patient. The aim of our study is to test whether these two molecules, glutamine and insulin used in combination attenuate the proinflammatory responses in endothelial cells which have been triggered by hyperglycaemia. Our results demonstrate that a combination of insulin and glutamine are significantly more effective in reducing the expression of IL-8, TNF-alpha and HO-1 than insulin or glutamine alone.

Matched MeSH terms: Tumor Necrosis Factor-alpha/metabolism
Endogenous tumor necrosis factor-alpha in patients with nasopharyngeal carcinoma

Yadav M

Southeast Asian J. Trop. Med. Public Health, 1991 Mar;22(1):123-6.
PMID: 1948253

Serum tumor necrosis factor alpha (TNF) concentration was assayed in 105 patients with nasopharyngeal carcinoma using a sensitive ELISA technique with detection level of 10 pg/ml. The TNF levels were detectable in 45 of 63 (71.4%) patients newly diagnosed for the malignancy and 29 of 42 (69%) patients in remission following treatment with radiotherapy. In 25 normal controls the TNF were less than 10 pg/ml. While TNF may be present in the majority of the patients with the malignant disease, the TNF concentration appeared to have no clinical significance in diagnosis or prognosis of the patients.

Matched MeSH terms: Tumor Necrosis Factor-alpha/metabolism*
Fulltext Effect of pentoxifylline on tumor necrosis factor-alpha and interleukin-6 levels in neonatal sepsis

Selim K, Hüseyin C, Ibrahim KH, Hasan BU, Kazim U, Hüseyin K

Med J Malaysia, 2004 Aug;59(3):391-4.
PMID: 15727386

Several pharmacological agents have been found to alter systemic concentrations and/or the activity of different cytokines via a variety of mechanisms, including changes in biosynthesis, secretion, and/or stability. Pentoxifylline (PTX), which is a methylxanthine derivative for example, has multiple effects on the immune system, but inhibition of pro-inflammatory cytokine release predominates. In this study we aimed to evaluate the influence of PTX on plasma levels of tumor necrosis factor (TNF) alpha and interleukin (IL)-6 in newborn infants with sepsis. The study included 20 infants with neonatal sepsis. In all subjects blood samples for serum C-reactive protein, TNF alpha and IL-6 determinations were received before giving PTX and at the 12th and 24th hours following PTX. In addition, white blood cell was counted before giving PTX and on the 3rd and 7th day following PTX. The infants were randomly divided into two groups. Firstly, PTX was used in infants who were successively admitted to the clinic and the subsequent infants were accepted as a control group. Of 20 infants, 13 infants received PTX and seven infants did not. We did not find any difference in the leukocyte count, serum C-reactive protein level, TNF alpha and IL-6 levels between the two groups of patients (P>0.05). While three infants died in the group of receiving PTX, death was not recorded in the group of non-receiving PTX (P>0.05). Our findings showed that PTX treatment did not affect leukocyte counts, serum CRP levels, TNF alpha and IL-6 levels and death ratio in newborn infants with sepsis. The last result may be due to the fact that the number of patients in the study was very small. We think that more extensive and controlled studies should be performed about this subject.

Matched MeSH terms: Tumor Necrosis Factor-alpha/metabolism
Fulltext Withaferin A protects against palmitic acid-induced endothelial insulin resistance and dysfunction through suppression of oxidative stress and inflammation

Batumalaie K, Amin MA, Murugan DD, Sattar MZ, Abdullah NA

Sci Rep, 2016 06 02;6:27236.
PMID: 27250532 DOI: 10.1038/srep27236

Activation of inflammatory pathways via reactive oxygen species (ROS) by free fatty acids (FFA) in obesity gives rise to insulin resistance and endothelial dysfunction. Withaferin A (WA), possesses both antioxidant and anti-inflammatory properties and therefore would be a good strategy to suppress palmitic acid (PA)-induced oxidative stress and inflammation and hence, insulin resistance and dysfunction in the endothelium. Effect of WA on PA-induced insulin resistance in human umbilical vein endothelial cells (HUVECs) was determined by evaluating insulin signaling mechanisms whilst effect of this drug on PA-induced endothelial dysfunction was determined in acetylcholine-mediated relaxation in isolated rat aortic preparations. WA significantly inhibited ROS production and inflammation induced by PA. Furthermore, WA significantly decreased TNF-α and IL-6 production in endothelial cells by specifically suppressing IKKβ/NF-κβ phosphorylation. WA inhibited inflammation-stimulated IRS-1 serine phosphorylation and improved the impaired insulin PI3-K signaling, and restored the decreased nitric oxide (NO) production triggered by PA. WA also decreased endothelin-1 and plasminogen activator inhibitor type-1 levels, and restored the impaired endothelium-mediated vasodilation in isolated aortic preparations. These findings suggest that WA inhibited both ROS production and inflammation to restore impaired insulin resistance in cultured endothelial cells and improve endothelial dysfunction in rat aortic rings.

Matched MeSH terms: Tumor Necrosis Factor-alpha/metabolism
Fulltext Palm Fruit Bioactives modulate human astrocyte activity in vitro altering the cytokine secretome reducing levels of TNFα, RANTES and IP-10

Weinberg RP, Koledova VV, Schneider K, Sambandan TG, Grayson A, Zeidman G, et al.

Sci Rep, 2018 Nov 06;8(1):16423.
PMID: 30401897 DOI: 10.1038/s41598-018-34763-3

Neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, are becoming more prevalent and an increasing burden on society. Neurodegenerative diseases often arise in the milieu of neuro-inflammation of the brain. Reactive astrocytes are key regulators in the development of neuro-inflammation. This study describes the effects of Palm Fruit Bioactives (PFB) on the behavior of human astrocytes which have been activated by IL-1β. When activated, the astrocytes proliferate, release numerous cytokines/chemokines including TNFα, RANTES (CCL5), IP-10 (CXCL10), generate reactive oxygen species (ROS), and express specific cell surface biomarkers such as the Intercellular Adhesion Molecule (ICAM), Vascular Cellular Adhesion Molecule (VCAM) and the Neuronal Cellular Adhesion Molecule (NCAM). Interleukin 1-beta (IL-1β) causes activation of human astrocytes with marked upregulation of pro-inflammatory genes. We show significant inhibition of these pro-inflammatory processes when IL-1β-activated astrocytes are exposed to PFB. PFB causes a dose-dependent and time-dependent reduction in specific cytokines: TNFα, RANTES, and IP-10. We also show that PFB significantly reduces ROS production by IL-1β-activated astrocytes. Furthermore, PFB also reduces the expression of ICAM and VCAM, both in activated and naïve human astrocytes in vitro. Since reactive astrocytes play an essential role in the neuroinflammatory state preceding neurodegenerative diseases, this study suggests that PFB may have a potential role in their prevention and/or treatment.

Matched MeSH terms: Tumor Necrosis Factor-alpha/metabolism*
Fulltext Lack of clinical manifestations in asymptomatic dengue infection is attributed to broad down-regulation and selective up-regulation of host defence response genes

Yeo AS, Azhar NA, Yeow W, Talbot CC, Khan MA, Shankar EM, et al.

PLoS One, 2014;9(4):e92240.
PMID: 24727912 DOI: 10.1371/journal.pone.0092240

Dengue represents one of the most serious life-threatening vector-borne infectious diseases that afflicts approximately 50 million people across the globe annually. Whilst symptomatic infections are frequently reported, asymptomatic dengue remains largely unnoticed. Therefore, we sought to investigate the immune correlates conferring protection to individuals that remain clinically asymptomatic.

Matched MeSH terms: Tumor Necrosis Factor-alpha/metabolism
Fulltext Gelam honey attenuates carrageenan-induced rat paw inflammation via NF-κB pathway

Hussein SZ, Mohd Yusoff K, Makpol S, Mohd Yusof YA

PLoS One, 2013;8(8):e72365.
PMID: 24015236 DOI: 10.1371/journal.pone.0072365

The activation of nuclear factor kappa B (NF-κB) plays a major role in the pathogenesis of a number of inflammatory diseases. In this study, we investigated the anti-inflammatory mechanism of Gelam honey in inflammation induced rats via NF-κB signalling pathway. Rats paw edema was induced by subplantar injection of 1% carrageenan into the right hind paw. Rats were pre-treated with Gelam honey at different doses (1 or 2 g/kg, p.o.) and NSAID Indomethacin (10 mg/kg, p.o.), in two time points (1 and 7 days). Our results showed that Gelam honey at both concentrations suppressed the gene expressions of NF-κB (p65 & p50) and IκBα in inflamed rats paw tissues. In addition, Gelam honey inhibited the nuclear translocation and activation of NF-κB and decreased the cytosolic degradation of IκBα dose dependently in inflamed rats paw tissues. The immunohistochemical expressions of pro-inflammatory mediators COX-2 and TNF-α were also decreased in inflamed rats paw tissues when treated with Gelam honey. The results of our findings suggest that Gelam honey exhibits its inhibitory effects by attenuating NF-κB translocation to the nucleus and inhibiting IκBα degradation, with subsequent decrease of inflammatory mediators COX-2 and TNF-α.

Matched MeSH terms: Tumor Necrosis Factor-alpha/metabolism
Fulltext Induction of apoptosis in human breast cancer cells via caspase pathway by vernodalin isolated from Centratherum anthelminticum (L.) seeds

Looi CY, Arya A, Cheah FK, Muharram B, Leong KH, Mohamad K, et al.

PLoS One, 2013;8(2):e56643.
PMID: 23437193 DOI: 10.1371/journal.pone.0056643

Centratherum anthelminticum (L.) seeds (CA) is a well known medicinal herb in Indian sub-continent. We recently reported anti-oxidant property of chloroform fraction of Centratherum anthelminticum (L.) seeds (CACF) by inhibiting tumor necrosis factor-α (TNF-α)-induced growth of human breast cancer cells. However, the active compounds in CACF have not been investigated previously.

Matched MeSH terms: Tumor Necrosis Factor-alpha/metabolism
Fulltext Attenuation of Inflammatory Mediators (TNF-α and Nitric Oxide) and Up-Regulation of IL-10 by Wild and Domesticated Basidiocarps of Amauroderma rugosum (Blume & T. Nees) Torrend in LPS-Stimulated RAW264.7 Cells

Chan PM, Tan YS, Chua KH, Sabaratnam V, Kuppusamy UR

PLoS One, 2015;10(10):e0139593.
PMID: 26427053 DOI: 10.1371/journal.pone.0139593

Amauroderma rugosum, commonly known as "Jiǎzī" in China, is a wild mushroom traditionally used by the Chinese to reduce inflammation, to treat diuretic and upset stomach, and to prevent cancer. It is also used by the indigenous communities in Malaysia to prevent epileptic episodes and incessant crying by babies. The aim of this study was to compare the wild and domesticated basidiocarps of A. rugosum for antioxidant and in vitro anti-inflammatory effects in LPS-stimulated RAW264.7 cells. The wild basidiocarps of A. rugosum were collected from the Belum Forest, Perak, Malaysia and the domesticated basidiocarps of A. rugosum were cultivated in the mushroom house located in the University of Malaya, Kuala Lumpur, Malaysia. Both the wild and domesticated basidiocarps were subjected to ethanolic extraction and the extracts were tested for antioxidant and anti-inflammatory activities. In this study, the crude ethanolic extract of wild (WB) and domesticated (DB) basidiocarps of A. rugosum had comparable total phenolic content and DPPH scavenging activity. However, WB (EC50 = 222.90 μg/mL) displayed a better ABTS cation radical scavenging activity than DB (EC50 = 469.60 μg/mL). Both WB and DB were able to scavenge nitric oxide (NO) radical and suppress the NO production in LPS-stimulated RAW264.7 cells and this effect was mediated through the down-regulation of inducible nitric oxide synthase (iNOS) gene. In addition, both WB and DB caused down-regulation of the inflammatory gene TNF-α and the up-regulation of the anti-inflammatory gene IL-10. There was no inhibitory effect of WB and DB on nuclear translocation of NF-κB p65. In conclusion, the wild and domesticated basidiocarps of A. rugosum possessed antioxidant and in vitro anti-inflammatory properties. WB and DB inhibited downstream inflammatory mediators (TNF-α and NO) and induced anti-inflammatory cytokine IL-10 production. No inhibitory effects shown on upstream nuclear translocation of NF-κB p65. WB and DB exhibited antioxidant activity and attenuation of proinflammatory mediators and therefore, A. rugosum may serve as a potential therapeutic agent in the management of inflammation.

Matched MeSH terms: Tumor Necrosis Factor-alpha/metabolism*
Fulltext Dynorphin 1-17 and Its N-Terminal Biotransformation Fragments Modulate Lipopolysaccharide-Stimulated Nuclear Factor-kappa B Nuclear Translocation, Interleukin-1beta and Tumor Necrosis Factor-alpha in Differentiated THP-1 Cells

Fazalul Rahiman SS, Morgan M, Gray P, Shaw PN, Cabot PJ

PLoS One, 2016;11(4):e0153005.
PMID: 27055013 DOI: 10.1371/journal.pone.0153005

Dynorphin 1-17, (DYN 1-17) opioid peptide produces antinociception following binding to the kappa-opioid peptide (KOP) receptor. Upon synthesis and release in inflamed tissues by immune cells, DYN 1-17 undergoes rapid biotransformation and yields a unique set of opioid and non-opioid fragments. Some of these major fragments possess a role in immunomodulation, suggesting that opioid-targeted therapeutics may be effective in diminishing the severity of inflammatory disorders. This study aimed to examine the immunomodulatory effects of DYN 1-17 and major N-terminal fragments found in the inflammatory environment on nuclear factor-kappaB/p65 (NF-κB/p65) nuclear translocation and the release of interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) from lipopolysaccharide (LPS)-stimulated, differentiated THP-1 cells. The results demonstrate that NF-κB/p65 nuclear translocation was significantly attenuated following treatment with DYN 1-17 and a specific range of fragments, with the greatest reduction observed with DYN 1-7 at a low concentration (10 nM). Antagonism with a selective KOP receptor antagonist, ML-190, significantly reversed the inhibitory effects of DYN 1-17, DYN 1-6, DYN 1-7 and DYN 1-9, but not other DYN 1-17 N-terminal fragments (DYN 1-10 and 1-11) on NF-κB/p65 nuclear translocation. DYN 1-17 and selected fragments demonstrated differential modulation on the release of IL-1β and TNF-α with significant inhibition observed with DYN 1-7 at low concentrations (1 nM and 10 pM). These effects were blocked by ML-190, suggesting a KOP receptor-mediated pathway. The results demonstrate that DYN 1-17 and certain N-terminal fragments, produced in an inflamed environment, play an anti-inflammatory role by inhibiting NF-κB/p65 translocation and the subsequent cytokine release through KOP receptor-dependent and independent pathways.

Matched MeSH terms: Tumor Necrosis Factor-alpha/metabolism*
Fulltext Stimulatory effects of polysaccharide fraction from Solanum nigrum on RAW 264.7 murine macrophage cells

Razali FN, Ismail A, Abidin NZ, Shuib AS

PLoS One, 2014;9(10):e108988.
PMID: 25299340 DOI: 10.1371/journal.pone.0108988

The polysaccharide fraction from Solanum nigrum Linne has been shown to have antitumor activity by enhancing the CD4+/CD8+ ratio of the T-lymphocyte subpopulation. In this study, we analyzed a polysaccharide extract of S. nigrum to determine its modulating effects on RAW 264.7 murine macrophage cells since macrophages play a key role in inducing both innate and adaptive immune responses. Crude polysaccharide was extracted from the stem of S. nigrum and subjected to ion-exchange chromatography to partially purify the extract. Five polysaccharide fractions were then subjected to a cytotoxicity assay and a nitric oxide production assay. To further analyze the ability of the fractionated polysaccharide extract to activate macrophages, the phagocytosis activity and cytokine production were also measured. The polysaccharide fractions were not cytotoxic, but all of the fractions induced nitric oxide in RAW 264.7 cells. Of the five fractions tested, SN-ppF3 was the least toxic and also induced the greatest amount of nitric oxide, which was comparable to the inducible nitric oxide synthase expression detected in the cell lysate. This fraction also significantly induced phagocytosis activity and stimulated the production of tumor necrosis factor-α and interleukin-6. Our study showed that fraction SN-ppF3 could classically activate macrophages. Macrophage induction may be the manner in which polysaccharides from S. nigrum are able to prevent tumor growth.

Matched MeSH terms: Tumor Necrosis Factor-alpha/metabolism
Fulltext Nickel(II) complex of polyhydroxybenzaldehyde N4-thiosemicarbazone exhibits anti-inflammatory activity by inhibiting NF-κB transactivation

Shawish HB, Wong WY, Wong YL, Loh SW, Looi CY, Hassandarvish P, et al.

PLoS One, 2014;9(6):e100933.
PMID: 24977407 DOI: 10.1371/journal.pone.0100933

BACKGROUND: The biological properties of thiosemicarbazone have been widely reported. The incorporation of some transition metals such as Fe, Ni and Cu to thiosemicarbazone complexes is known to enhance its biological effects. In this study, we incorporated nickel(II) ions into thiosemicarbazone with N4-substitution groups H3L (H; H3L1, CH3; H3L2, C6H5; H3L3 and C2H5; H3L4) and examined its potential anti-inflammatory activity.
METHODOLOGY/PRINCIPAL FINDINGS: Four ligands (1-4) and their respective nickel-containing complexes (5-8) were synthesized and characterized. The compounds synthesized were tested for their effects on NF-κB nuclear translocation, pro-inflammatory cytokines secretion and NF-κB transactivation activity. The active compound was further evaluated on its ability to suppress carrageenan-induced acute inflammation in vivo. A potential binding target of the active compound was also predicted by molecular docking analysis.
CONCLUSIONS/SIGNIFICANCE: Among all synthesized compounds tested, we found that complex [Ni(H2L1)(PPh3)]Cl (5) (complex 5), potently inhibited IκBα degradation and NF-κB p65 nuclear translocation in LPS-stimulated RAW264.7 cells as well as TNFα-stimulated HeLa S3 cells. In addition, complex 5 significantly down-regulated LPS- or TNFα-induced transcription of NF-κB target genes, including genes that encode the pro-inflammatory cytokines TNFα, IFNβ and IL6. Luciferase reporter assays confirmed that complex 5 inhibited the transactivation activity of NF-κB. Furthermore, the anti-inflammatory effect of complex 5 was also supported by its suppressive effect on carrageenan-induced paw edema formation in wild type C57BL/6 mice. Interestingly, molecular docking study showed that complex 5 potentially interact with the active site of IKKβ. Taken together, we suggest complex 5 as a novel NF-κB inhibitor with potent anti-inflammatory effects.

Matched MeSH terms: Tumor Necrosis Factor-alpha/metabolism
Antimicrobial efficacy of indocyanine green-mediated photodynamic therapy compared with Salvadora persica gel application in the treatment of moderate and deep pockets in periodontitis

Niazi FH, Noushad M, Tanvir SB, Ali S, Al-Khalifa KS, Qamar Z, et al.

Photodiagnosis Photodyn Ther, 2020 Mar;29:101665.
PMID: 31978565 DOI: 10.1016/j.pdpdt.2020.101665

BACKGROUND: In order to prove the idea that topical application of drugs can improve the clinical parameters affecting periodontal disease, a sound comparison should be made between topical therapeutic models. The aim of the present study was to assess the clinical efficacy of photodynamic therapy (PDT) and Salvadora persica (SP) gel as adjuncts to scaling and root planning (SRP) in the treatment of chronic periodontitis.
METHODS: The selected patients were divided into three groups, Group I (PDT + SRP), Group II (SP + SRP) and group III (SRP alone). Clinical inflammatory periodontal parameters including plaque index (PI), bleeding on probing (BOP), probing depth (PD) and clinical attachment level (CAL) gain were assessed. Assessment of crevicular fluid interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α) was performed using enzyme-linked immunosorbent assay technique. All measurements were recorded at baseline, 3 months and 6 months follow-up periods, respectively.
RESULTS: A total of 73 patients completed the study. A significant improvement in the BOP was seen in Group II at both follow up visits when compared with other groups (p < 0.05). Only in Group-I that showed statistically significant reduction in moderate periodontal pockets at 3 months (p = 0.021), and significant reductions in deep pockets at 3-months (p = 0.003) and 6-months (p = 0.002), respectively. CAL gain also was reported to be seen in group-I at both visits (p < 0.05). Group- I and II significantly reduced the levels of IL-6 at 3-month period compared to Group-III. This reduction was further maintained by group-II and group-III at 6 months, respectively. TNF-α showed statistically significant decrease in Group II as compared to Group I and Group-III and this reduction was maintained by the end of 6-month visit (p = 0.045).
CONCLUSION: Both the treatment modalities PDT and SP helped in reducing periodontal inflammation. PDT reported significant gain in clinical attachment level, whereas the SP significantly reduced the bleeding levels.

Matched MeSH terms: Tumor Necrosis Factor-alpha/metabolism
Novel Fish Oil-based Bigel System for Controlled Drug Delivery and its Influence on Immunomodulatory Activity of Imiquimod Against Skin Cancer

Rehman K, Zulfakar MH

Pharm Res, 2017 01;34(1):36-48.
PMID: 27620176 DOI: 10.1007/s11095-016-2036-8

PURPOSE: To characterize bigel system as a topical drug delivery vehicle and to establish the immunomodulatory role of imiquimod-fish oil combination against skin cancer and inflammation resulting from chemical carcinogenesis.
METHODS: Imiquimod-loaded fish oil bigel colloidal system was prepared using a blend of carbopol hydrogel and fish oil oleogel. Bigels were first characterized for their mechanical properties and compared to conventional gel systems. Ex vivo permeation studies were performed on murine skin to analyze the ability of the bigels to transport drug across skin and to predict the release mechanism via mathematical modelling. Furthermore, to analyze pharmacological effectiveness in skin cancer and controlling imiquimod-induced inflammatory side effects, imiquimod-fish oil combination was tested in vitro on epidermoid carcinoma cells and in vivo in Swiss albino mice cancer model.
RESULTS: Imiquimod-loaded fish oil bigels exhibited higher drug availability inside the skin as compared to individual imiquimod hydrogel and oleogel controls through quasi-Fickian diffusion mechanism. Imiquimod-fish oil combination in bigel enhanced the antitumor effects and significantly reduced serum pro-inflammatory cytokine levels such as tumor necrosis factor-alpha and interleukin-6, and reducing tumor progression via inhibition of vascular endothelial growth factor. Imiquimod-fish oil combination also resulted in increased expression of interleukin-10, an anti-inflammatory cytokine, which could also aid anti-tumor activity against skin cancer.
CONCLUSION: Imiquimod administration through a bigel vehicle along with fish oil could be beneficial for controlling imiquimod-induced inflammatory side effects and in the treatment of skin cancer.

Matched MeSH terms: Tumor Necrosis Factor-alpha/metabolism
Agarwood oil nanoemulsion counteracts LPS-induced inflammation and oxidative stress in RAW264.7 mouse macrophages

Malik R, Paudel KR, Manandhar B, De Rubis G, Shen J, Mujwar S, et al.

Pathol Res Pract, 2023 Nov;251:154895.
PMID: 37879146 DOI: 10.1016/j.prp.2023.154895

PURPOSE: Oxidative stress and inflammation are key pathophysiological features of chronic respiratory diseases, including asthma and chronic obstructive pulmonary disease (COPD). Agarwood oil obtained from Aquilaria trees has promising antioxidant and anti-inflammatory activities. However, its clinical application is hampered by poor solubility. A viable approach to overcome this involves formulation of oily constituents into emulsions. Here, we have investigated the antioxidant and anti-inflammatory potential of an agarwood oil-based nanoemulsion (DE'RAAQSIN) against lipopolysaccharide (LPS)-induced RAW264.7 mouse macrophages in vitro.
METHODS: The antioxidant and anti-inflammatory activity of DE'RAAQSIN was assessed by measuring the levels of ROS and nitric oxide (NO) produced, using the DCF-DA assay and the Griess reagent assay, respectively. The molecular pathways activated by DE'RAAQSIN were investigated via qPCR.
RESULTS: LPS stimulation of RAW264.7 cells increased the production of nitric oxide (NO) and ROS and resulted in the overexpression of the inducible nitric oxide synthase (iNOS) gene. Furthermore, LPS induced the upregulation of the expression of key proinflammatory genes (IL-6, TNF-α, IL-1β, and CXCL1) and of the antioxidant gene heme oxygenase-1 (HO-1). DE'RAAQSIN demonstrated potent antioxidant and anti-inflammatory activity by significantly reducing the levels of ROS and of secreted NO, simultaneously counteracting the LPS-induced overexpression of iNOS, IL-6, TNF-α, IL-1β, and HO-1. These findings were corroborated by in silico activity prediction and physicochemical analysis of the main agarwood oil components.
CONCLUSIONS: We propose DE'RAAQSIN as a promising alternative managing inflammatory disorders, opening the platform for further studies aimed at understanding the effectiveness of DE'RAAQSIN.

Matched MeSH terms: Tumor Necrosis Factor-alpha/metabolism
Total Protein Concentration and Tumor Necrosis Factor α in Tears of Nonproliferative Diabetic Retinopathy

Amil-Bangsa NH, Mohd-Ali B, Ishak B, Abdul-Aziz CNN, Ngah NF, Hashim H, et al.

Optom Vis Sci, 2019 12;96(12):934-939.
PMID: 31834153 DOI: 10.1097/OPX.0000000000001456

SIGNIFICANCE: Total protein concentration (TPC) and tumor necrosis factor α (TNF-α) concentration in tears are correlated with severity of retinopathy. However, minimal data are available in the literature for investigating tear TPC and TNF-α concentrations in Asian individuals with different severity of nonproliferative diabetic retinopathy (NPDR).
PURPOSE: This study evaluated differences of TPC and TNF-α concentrations in tears at different severity of NPDR among participants with diabetes in comparison with normal participants.
METHODS: A total of 75 participants were categorized based on Early Treatment for Diabetic Retinopathy Study scale, with 15 participants representing each group, namely, normal, diabetes without retinopathy, mild NPDR, moderate NPDR, and severe NPDR. All participants were screened using McMonnies questionnaire. Refraction was conducted subjectively. Visual acuity was measured using a LogMAR chart. Twenty-five microliters of basal tears was collected using glass capillary tubes. Total protein concentration and TNF-α concentrations were determined using Bradford assay and enzyme-linked immunosorbent assay, respectively.
RESULTS: Mean ± SD age of participants (n = 75) was 57.88 ± 4.71 years, and participants scored equally in McMonnies questionnaire (P = .90). Mean visual acuity was significantly different in severe NPDR (P = .003). Mean tear TPC was significantly lower, and mean tear TNF-α concentration was significantly higher in moderate and severe NPDR (P < .001). Mean ± SD tear TPC and TNF-α concentrations for normal were 7.10 ± 1.53 and 1.39 ± 0.24 pg/mL; for diabetes without retinopathy, 6.37 ± 1.65 and 1.53 ± 0.27 pg/mL; for mild NPDR, 6.32 ± 2.05 and 1.60 ± 0.21 pg/mL; for moderate NPDR, 3.88 ± 1.38 and 1.99 ± 0.05 pg/mL; and for severe NPDR, 3.64 ± 1.26 and 2.21 ± 0.04 pg/mL, respectively. Tear TPC and TNF-α concentrations were significantly correlated (r = -0.50, P < .0001). Visual acuity was significantly correlated with tear TPC (r = -0.236, P = .04) and TNF-α concentrations (r = 0.432, P < .0001).
CONCLUSIONS: This cross-sectional study identified differences in tear TPC and TNF-α concentrations with increasing severity of NPDR.

Matched MeSH terms: Tumor Necrosis Factor-alpha/metabolism*

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