The Role of Heme Oxygenase 1 in Rheumatoid Arthritis and IL-1 Induced Inflammatory Cell Model.

OBJECTIVE: Rheumatoid arthritis (RA) is a common chronic autoimmune inflammatory disease. The pathogenesis of RA is complex, and RA lacks effective therapeutic drugs. Heme oxygenase 1 (HO-1) is found to be reduced in RA. However, the role of HO-1 in RA and related mechanisms have not been elucidated. METHODS: RA rat model was established. The expression of HO-1 was upregulated by hemin. The increase weight rate, the degree of toe swelling, and the arthritis index were analyzed to evaluate the therapeutic effect of HO-1 on RA. In vitro RAW264.7 inflammatory cell model was established using 5 ng/mL IL-1. SnPP or hemin were used to inhibit or upregulate HO-1 expression. Tetrazolium salt colorimetric assay (MTT) was selected to test cell proliferation. ELISA was used to determine the concentrations of cellular inflammatory factors IL-1 and IL-6. Reactive oxygen species (ROS) activity was assessed. Western blot was performed to analyze NF-[Formula: see text]B and MMP-3 expressions. RESULTS: The expression of HO-1 was decreased in RA rats, and hemin increased HO-1 level in arthritic rats, which elevated the increase weight rate and decreased toe swelling degree and arthritis index (P<0.05). Hemin significantly upregulated HO-1 expression, inhibited inflammatory cell proliferation, decreased IL-1 and IL-6 expressions, declined ROS level, restrained NF-[Formula: see text]B expression, and enhanced MMP-3 expression in Raw264.7 cells induced by LPS (P<0.05). SnPP obviously inhibited the expression of HO-1, promoted cell proliferation, elevated IL-1 and IL-6 secretions, increased ROS level, promoted NF-[Formula: see text]B expression, and decreased MMP-3 level compared with LPS group (P<0.05). CONCLUSION: Upregulation of HO-1 can improve arthritis symptoms by reducing ROS expression, inhibiting NF-[Formula: see text]B signaling pathway, elevating MMP-3 expression, attenuating inflammatory factor secretion, and suppressing inflammatory cell proliferation.

Silibinin Mitigates Vanadium-induced Lung Injury via the TLR4/MAPK/NF-κB Pathway in Mice.

BACKGROUND/AIM: Silibinin, has been investigated for its potential benefits and mechanisms in addressing vanadium pentoxide (V2O5)-induced pulmonary inflammation. This study explored the anti-inflammatory activity of silibinin and elucidate the mechanisms by which it operates in a mouse model of vanadium-induced lung injury. MATERIALS AND METHODS: Eight-week-old male BALB/c mice were exposed to V2O5 to induce lung injury. Mice were pretreated with silibinin at doses of 50 mg/kg and 100 mg/kg. Histological analyses were performed to assess cell viability and infiltration of inflammatory cells. The expression of pro-inflammatory cytokines (TNF-α, IL-6, IL-1ß) and activation of the MAPK and NF-[Formula: see text]B signaling pathways, as well as the NLRP3 inflammasome, were evaluated using real-time PCR, western blot analysis, and immunohistochemistry. Whole blood analysis was conducted to measure white blood cell counts. RESULTS: Silibinin treatment significantly improved cell viability, reduced inflammatory cell infiltration, and decreased the expression of pro-inflammatory cytokines in V2O5-induced lung injury. It also notably suppressed the activation of the MAPK and NF-[Formula: see text]B signaling pathways, along with a marked reduction in NLRP3 inflammasome expression levels in lung tissues. Additionally, silibinin-treated groups exhibited a significant decrease in white blood cell counts, including neutrophils, lymphocytes, and eosinophils. CONCLUSION: These findings underscore the potent anti-inflammatory effects of silibinin in mice with V2O5-induced lung inflammation, highlighting its therapeutic potential. The study not only confirms the efficacy of silibinin in mitigating inflammatory responses but also provides a foundational understanding of its role in modulating key inflammatory pathways, paving the way for future therapeutic strategies against pulmonary inflammation induced by environmental pollutants.

The Important Role of GPX1 and NF-κB Signaling Pathway in Human Gastric Cancer: Implications for Cell Proliferation and Invasion.

BACKGROUND/AIM: Glutathione peroxidases (GPXs) are crucial antioxidant enzymes, counteracting reactive oxygen species (ROS). GPX overexpression promotes proliferation and invasion in cancer cells. Glutathione peroxidase-1 (GPX1), the most abundant isoform, contributes to invasion, migration, cisplatin resistance, and proliferation in various cancers. Nuclear factor-kappa B (NF-[Formula: see text]B) participates in cell proliferation, apoptosis, and tumor progression. The inhibition of NF-[Formula: see text]B expression reduces the malignancy of esophageal squamous cell carcinoma. This study aimed to explore the GPX1 and NF-[Formula: see text]B signaling pathways and their correlation with gastric cancer cell proliferation and invasion. MATERIALS AND METHODS: Cell culture, complementary DNA microarray analysis, western blotting, reverse transcription-polymerase chain reaction, zymography, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, GPX1 knock-down with short hairpin RNA (shRNA), standard two-chamber invasion assay, chromatin immunoprecipitation assay. RESULTS: Hepatocyte growth factor (HGF) up-regulated GPX1 expression in gastric cancer cells. The NF-[Formula: see text]B inhibitor, pyrrolidine dithiocarbamate down-regulated HGF-induced GPX1 protein levels. Furthermore, NF-[Formula: see text]B and urokinase-type plasminogen activators were down-regulated in GPX1-shRNA-treated cells. Treatment with an Akt pathway inhibitor (LY294002) led to the down-regulation of GPX1 and NF-[Formula: see text]B gastric cancer cells. GPX1 knockdown resulted in decreased HGF-mediated in vitro cell proliferation and invasion. The study identified the putative binding site of the GPX1 promoter containing the NF-[Formula: see text]B binding site, confirmed through chromatin immunoprecipitation. CONCLUSION: HGF induced GPX1 expression through the NF-[Formula: see text]B and Akt pathways, suggesting a central role in gastric cell proliferation and invasion. Hence, GPX1 emerges as a potential therapeutic target for gastric cancer.

Jeduxiaoliu Formula can Induce Apoptosis of Lymphoma Cells In Vitro and In Vivo.

OBJECTIVE: Lymphoma is the most common malignancy of the haematological system. Jeduxiaoliu formula (JDXLF) exerts good therapeutic effects against lymphoma, however, the mechanisms underlying these effects remain unclear. Therefore, this study aimed to investigate the mechanism of action of JDXLF. METHOD: RNA-Seq was performed to examine the molecular mechanisms underlying the therapeutic effects of JDXLF against lymphoma. CCK-8 assay was performed to examine the effects of JDXLF on the proliferation of lymphoma cells. Electron microscopy was performed to examine the morphology of lymphoma cells. Flow cytometry was performed to examine the apoptosis and cell cycle of lymphoma cells. qPCR and Western blotting were performed to detect the expression of apoptotic genes and proteins. In vivo, the tumour-suppressive effect of JDXLF on lymphoma transplanted tumours was examined by establishing a subcutaneous transplantation tumour model in nude mice, and the expression of apoptotic proteins in tumour tissues was analysed via immunohistochemical staining. RESULTS: RNA-Seq revealed 71, 350 and 620 differentially expressed genes (DEGs) in the 1mg/mL, 4mg/mL and 8mg/mL JDXLF treatment groups, respectively. KEGG pathway analysis showed that the DEGs were significantly associated with apoptosis, TNF signalling and NF-κB signalling. In vitro experiments revealed that JDXLF inhibited the proliferation of lymphoma (Raji and Jeko-1) cells in a dose-dependent manner, induced apoptosis and upregulated the expression of Bax/Bcl-2 and caspase3. In vivo experiments revealed that JDXLF had a significant tumourshrinking effect on mice and increased the expression of the apoptosis-related proteins caspase3 and Bax/Bcl-2. CONCLUSIONS: This study indicates that JDXLF can induce apoptosis in lymphoma cells in vitro and in vivo. We suggest this may provide a direction for further research into lymphoma therapy.

Effects of aerobic exercise on myocardial injury, NF-B expression, glucolipid metabolism and inflammatory factors in rats with coronary heart disease

Abstract Objective To investigate the influence of aerobic exercise on myocardial injury, NF-B expression, glucolipid metabolism and inflammatory factors in rats with Coronary Heart Disease (CHD) and explore the possible causative role. Methods 45 Sprague Dawley® rats were randomized into model, control and experimental groups. A high-fat diet was adopted for generating a rat CHD model, and the experimental group was given a 4-week aerobic exercise intervention. ECG was utilized to evaluate the cardiac function of the rats; HE staining to evaluate the damage of myocardial tissue; TUNEL staining to evaluate cardiomyocyte apoptosis level; ELISA to assay the contents of inflammatory factors and glucolipid metabolism in cardiomyocytes; qPCR to assay IB- and NF-B mRNA expression; Western-blot to assay the apoptosis-related proteins and NF-B signaling pathway-related proteins expressions in myocardial tissue. Results In contrast to the model group, aerobic exercise strongly improved the rat's cardiac function and glucolipid metabolism (p < 0.01), enhanced IL-10 content, Bcl-2/Bax level as well as IB- protein and mRNA expression (p < 0.01), and reduced myocardial injury and cardiomyocyte apoptosis, the contents of IL-6, IL-1 and TNF-, Caspase 3 level, NF-B mRNA and protein expression and p-p38 and p-STAT3 expressions (p < 0.01). Conclusion Aerobic exercise can not only effectively reduce myocardial injury, the release of inflammatory factors and NF-B expression in CHD rats, but also improve cardiac function and glucolipid metabolism. Its mechanism is likely to be related to the inhibition of the NF-B signaling pathway.

The Role of CDK20 Protein in Carcinogenesis.

Cancer is a complex disease that develops when abnormal cells divide uncontrollably as a consequence of unregulated cell cycle protein activity. Therefore, the cell cycle is crucial for maintaining homeostasis inside the cells during DNA replication and cell division. The presence of mutations within specific genes can disrupt the equilibrium within cells, ultimately leading to the growth of cancer. CDK20 (Cyclin-Dependent Kinase 20) is recently identified as a major controller of cell cycle checkpoints, which regulate cell growth and proliferation and perform a role in the development of many malignancies. CCRK (Cell-Cycle Related Kinase) has recently been renamed CDK20. Emerging studies proclaimed that the upregulation of CDK20 was identified in cancers of the ovary, brain, colon, stomach, liver, and lung. CDK20 was thought to have Cyclin-dependent activating kinase (CAK) activity for CDK2 when it is complexed with Cyclin H. Furthermore, recent studies revealed that CDK20 is involved in the Wnt, EZH2/NF-B, and KEAP1-NRF2 signaling pathways, all of which are interconnected to cancer formation and proliferation. In addition, the structure of CDK20 was predicted using ColabFold, a powerful software integrating AlphaFold's advanced AI system. The present review focuses on a systematic overview of the current knowledge on CDK20 derived from in vitro and in vivo studies and emphasizes its role in carcinogenesis. The validation comparison of the existing CDK20 AlphaFold structure with the ColabFold was found to be exceptionally fast and accurate in generating reliable models.

The role of histone deacetylases in NLRP3 inflammasomes-mediated epilepsy.

Epilepsy is one of the most common brain disorders that not only causes death worldwide, but also affects the daily lives of patients. Previous studies have revealed that inflammation plays an important role in the pathophysiology of epilepsy. Activation of inflammasomes can promote neuroinflammation by boosting the maturation of caspase-1 and the secretion of various inflammatory effectors, including chemokines, interleukins, and tumor necrosis factors. With the in-depth research on the mechanism of inflammasomes in the development of epilepsy, it has been discovered that NLRP3 inflammasomes may induce epilepsy by mediating neuronal inflammatory injury, neuronal loss and blood-brain barrier dysfunction. Therefore, blocking the activation of the NLRP3 inflammasomes may be a new epilepsy treatment strategy. However, the drugs that specifically block NLRP3 inflammasomes assembly has not been approved for clinical use. In this review, the mechanism of how HDACs, an inflammatory regulator, regulates the activation of NLRP3 inflammasome is summarized. It helps to explore the mechanism of the HDAC inhibitors inhibiting brain inflammatory damage so as to provide a potential therapeutic strategy for controlling the development of epilepsy.

PKR-NF-κB Pathway Upstream of IFN-ß Induction Is Dysregulated in Oncolytic Sindbis Virus-infected HeLa Cells.

BACKGROUND/AIM: Sindbis virus (SINV) is a naturally occurring oncolytic virus that kills cancer cells and is less harmful to normal cells. In this study, a recombinant SINV, which expressed green and blue fluorescent proteins, was used to precisely analyze SINV infection and replication. MATERIALS AND METHODS: Antiviral responses, including IFN-ß mRNA, protein kinase R (PKR), NF-B, and caspase 3/7, were analyzed in SINV-infected cancerous HeLa cells and normal human fibroblast TIG-1-20 cells. RESULTS: SINV could infect, replicate, and proliferate both in HeLa and TIG-1-20 cells, causing lytic infection only in HeLa cells. SINV grew preferentially in HeLa cells causing remarkable apoptosis. IFN-ß mRNA expression was suppressed in SINV-infected HeLa cells compared to that in TIG-1-20 cells. Further analyses of PKR and NF-B upstream of IFN-ß induction revealed that the compromised response in the PKR-NF-B pathway during early infection coincided with IFN induction suppression in HeLa cells. CONCLUSION: Dysregulation of PKR in HeLa cells is the determinant of SINV oncolysis.

Dimethyl Fumarate Suppresses the Proliferation of HTLV-1-infected T Cells by Inhibiting CBM Complex-triggered NF-B Signaling.

BACKGROUND/AIM: Adult T-cell leukemia (ATL) is a peripheral T-lymphocytic malignancy influenced by human T-cell leukemia virus type 1 (HTLV-1) infection. Aggressive ATL has a poor prognosis, therefore newer agents are desperately needed. We revealed that dimethyl fumarate (DMF) causes ATL cell death via inhibition of nuclear factor-kappa B (NF-B) and signal transducer and activator of transcription 3 signaling. Here, we evaluated the specific mechanism of DMF effects on NF-B signaling in MT-2 HTLV-1-infected T-cells. MATERIALS AND METHODS: We examined the effects of DMF on the caspase recruitment domain family member 11 (CARD11)-BCL10 immune signaling adaptor (BCL10)-mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) (CBM) complex and upstream signaling molecules which are critical for NF-B signaling in MT-2 cells by immunoblotting. We also explored its effects on cell-cycle distribution. Furthermore, we assessed whether the BCL2 apoptosis regulator (BCL2)/BCL2-like 1 (BCL-xL) inhibitor navitoclax promoted the inhibitory effect of DMF on cell proliferation and apoptosis-associated proteins by trypan blue exclusion test and immunoblotting, respectively. RESULTS: DMF inhibited constitutive phosphorylation of CARD11 followed by suppression of inhibitory-B kinase α/ß phosphorylation at serine in a dose-dependent fashion in MT-2 cells. Furthermore, DMF inhibited MALT1 and BCL10 expression in the same fashion. However, DMF did not prevent the phosphorylation of protein kinase C-ß, an upstream signaling molecule of CARD11. Cell-cycle analysis highlighted that DMF treatment at 75 µM resulted in the accumulation of cells at the sub-G1 and G2/M phases. Navitoclax modestly promoted DMF-induced suppression of MT-2 cells via inhibition of cellular inhibitor of apoptosis protein-2 expression and c-JUN N-terminal kinase phosphorylation. CONCLUSION: The suppression of MT-2 cell proliferation by DMF makes its further evaluation as an innovative agent for therapy of ATL worthwhile.

Inflammatory Response Modulation by Low-Dose Anti-inflammatory Drugs Treatment in an in vitro Osteoarthritis Cellular Model.

BACKGROUND: Low-dose-medicine is based on the administration of low doses of biological regulators to restore the immunologic balance altered in the disease. Cytokines are pivotal regulators of cellular and tissue functions and impaired crosstalk, due to an imbalance between specific cytokines, it is fundamental in acute inflammation and diseases correlated to low-grade chronic inflammation. Osteoarthritis is the most prevalent arthritic disease and a leading cause of disability. In the treatment of muscle-skeletal pathologies, the therapeutic integration of conventional medicine with homotoxicology, or low-dose-medicine appears to be beneficial. OBJECTIVE: This study aims to get more insights into the role of inflammatory cytokines and chemokines during the development of osteoarthritis and to evaluate a possible blocking strategy using anti-inflammatory molecules, we resort to an in vitro experimental model using an established human chondrosarcoma cell line that underwent to a well known pro-inflammatory stimulus as bacterial lipopolysaccharide. METHOD: We tested the production of inflammatory-related cytokines and chemokines, and the efficacy of low-dose (LD) administration of anti-inflammatory compounds, namely IL-10 and anti-IL-1, to block inflammatory cellular pathways. RESULTS: Following an inflammatory insult, chondrocytes upregulated the expression of several pro-inflammatory cyto-/chemokines and this induction could be counteracted by LD IL-10 and anti-IL-1. We reported that these effects could be ascribed to an interfering effect of LD drugs with the NF-κB signaling. CONCLUSION: Our results provided a good indication that LD drugs can be effective in inhibiting the inflammatory response in chondrocytes opening the way to new therapies for the treatment of diseases such as osteoarthritis.

MAP7 Promotes Breast Cancer Cell Migration and Invasion by Regulating the NF-B Pathway.

OBJECTIVE: To investigate and explore the molecular mechanisms of MAP7 on breast cancer cell migration and invasion. METHODS: The MAP7 transcript data in TCGA database was firstly statistically analyzed. Then, immunohistochemistry and western blot assays were applied to check MAP7 expression levels in breast cancer tissues or cell lines. EdU immunofluorescent staining assay was applied to reveal the cell proliferation of breast cancer cells after knockdown or overexpression of MAP7. Scratch and Transwell assays were applied to observe cell invasion and migration after knockdown or overexpression of MAP7. The western blot assays were employed to prove the expression levels of NF-B p65 and IBα after knockdown or overexpression of MAP7. Finally, breast xenograft model was established to verify the tumor volume and weight in mice. RESULTS: The results indicated the mRNA and protein expression of MAP7 was higher in breast cancer tissues or cell lines than that in normal tissue or normal breast epithelial cells, respectively. MAP7 promoted proliferation, migration, and invasion of breast cancer cells. Knockdown or overexpression of MAP7 in breast cancer cells would inhibit or promote phosphorylation of NF-B p65 and IBα protein. Finally, MAP7 can also promote tumor growth in mice. CONCLUSIONS: MAP7 facilitated breast cancer cell migration and invasion by regulating the NF-B pathway.

Magnolol Suppresses ERK/NF-κB Signaling and Triggers Apoptosis Through Extrinsic/Intrinsic Pathways in Osteosarcoma.

BACKGROUND/AIM: Osteosarcoma is an aggressive primary malignant bone tumor that occurs in childhood. Although the diagnostic and treatment options have been improved, osteosarcoma confers poor prognosis. Magnolol, an active component of Magnoliae officinalis cortex, has been widely applied in herb medicine and has been shown to have multiple pharmacological activities. However, whether magnolol possesses anti-osteosarcoma capacity remains unknown. MATERIALS AND METHODS: We examined magnolol is cytotoxicity, and whether it regulates apoptosis and oncogene expression using MTT, flow cytometry and Western blotting assays in osteosarcoma cells. RESULTS: Magnolol exerted toxicity towards U-2 OS cells by inducing intrinsic/extrinsic apoptosis pathways. Additionally, treatment of U-2 OS cells with magnolol inhibited MAPK1 mitogen-activated protein kinase 1 (ERK)/Nuclear factor kappa B (NF-B) signaling involved in tumor progression and reduced the expression of anti-apoptotic and metastasis-associated genes. CONCLUSION: Magnolol may induce apoptosis and inactivate ERK/NF-B signal transduction in osteosarcoma cells.

MiR-96-5p induced NDRG1 deficiency promotes prostate cancer migration and invasion through regulating the NF-κB signaling pathway.

OBJECTIVE: The N-myc downstream-regulated gene 1 (NDRG1) has been discovered as a significant gene in the progression of cancers. However, the regulatory mechanism of NDRG1 remained obscure in prostate cancer (PCa). METHODS: The miR-96-5p and NDRG1 expression levels were evaluated in PCa cell lines, prostate tissues, and validated public databases by real-time PCR, western blot analysis, and immunohistochemistry. The function of miR-96-5p and NDRG1 were investigated by wound healing and transwell assays in vitro, and mouse xenograft assay in vivo. The candidate pathway regulated by NDRG1 was conducted by the next-generation gene sequencing technique. Immunofluorescence and luciferase assay was used to detect the relation between miR-96-5p, NDRG1, and NF-κB pathway. RESULTS: Overexpressing NDRG1 suppresses the migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro, and inhibits metastasis in vivo. Moreover, miR-96-5p contributes to NDRG1 deficiency and promotes PCa cell migration and invasion. Furthermore, NDRG1 loss activates the NF-κB pathway, which stimulates p65 and IKBa phosphorylation and induces EMT in PCa. CONCLUSIONS: MiR-96-5p promotes the migration and invasion of PCa by targeting NDRG1 and regulating the NF-κB pathway.

Magnolol Induces Apoptosis Through Extrinsic/intrinsic Pathways and Attenuates NF-κB/STAT3 Signaling in Non-small-cell Lung Cancer Cells.

BACKGROUND/AIM: Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer worldwide, and treatment outcomes are still poor. Magnolol, a hydroxylated biphenyl isolated from Magnolia officinalis, was found to be effective against hepatocellular carcinoma via inactivating nuclear-factor-kappa B (NF-B) signaling. However, whether magnolol targets not only NF-B but also other factors in NSCLC and may contribute to the suppression of tumor progression is unclear. MATERIALS AND METHODS: Cell viability, flow cytometry, and western blotting assays were used to identify the mechanism of magnolol action in human lung adenocarcinoma cell lines A549 and CL1-5-F4. RESULTS: Our results indicated that magnolol induced cytotoxicity through extrinsic/intrinsic apoptosis signaling and suppressed phosphorylation of signal transducer and activator of transcription 3 (STAT3)/NF-B and expression of their downstream proteins. CONCLUSION: Magnolol not only induced extrinsic and intrinsic apoptosis signaling but also inactivated STAT3/NF-B and attenuated their signaling of epithelial-mesenchymal transition and metastasis-related protein expression in NSCLC.

Cardioprotective Potential of Garlic Oil and Its Active Constituent, Diallyl Disulphide, in Presence of Carvedilol during Chronic Isoprenaline Injection-Mediated Myocardial Necrosis in Rats.

In isoprenaline (ISO)-induced myocardial infarcted rats, garlic oil (GO) and its main ingredient, diallyl disulfide (DADS), were examined for cardioprotective effects when used with carvedilol (CAR). GO, DADS and CAR were given to rats in their respective groups, either alone or together, with the addition of isoprenaline (3 mg/kg/day, subcutaneously) during the last 10 days of treatment. At the end of 14 days of treatment, blood samples were collected, the hearts were excised under anesthesia and weighed. Heart tissue homogenate was used to measure superoxide dismutase (SOD), catalase (CAT), and thiobarbituric acid reactive substances (TBARS). Furthermore, the serum activities of cardiac markers, including lactate dehydrogenase, creatine kinase, and cardiac troponin, were checked. Moreover, inflammatory markers including tumor necrosis factor alpha, interleukin one beta, interleukin six, and kappa bp65 subunit were assessed. Rats that received GO, DADS, and CAR exhibited a significant increase in the cardiac antioxidant enzyme activities with a simultaneous decrease in serum cardiac markers enzymes and inflammatory markers. The TBARS were significantly reduced in rats that received treatment. The addition of carvedilol to GO or DADS significantly elevated antioxidant activities and decreased the release of cardiac enzymes into blood circulation. Both DADS and GOl were almost similar in efficacy, indicating the potential role of DADS in garlic oil-mediated cardioprotection. Combining GO or DADS with CAR increased CAR's cardioprotective impact and protected rats from developing ISO-induced myocardial infarction.

Metronomic 5-Fluorouracil Delivery Primes Skeletal Muscle for Myopathy but Does Not Cause Cachexia.

Skeletal myopathy encompasses both atrophy and dysfunction and is a prominent event in cancer and chemotherapy-induced cachexia. Here, we investigate the effects of a chemotherapeutic agent, 5-fluorouracil (5FU), on skeletal muscle mass and function, and whether small-molecule therapeutic candidate, BGP-15, could be protective against the chemotoxic challenge exerted by 5FU. Additionally, we explore the molecular signature of 5FU treatment. Male Balb/c mice received metronomic tri-weekly intraperitoneal delivery of 5FU (23 mg/kg), with and without BGP-15 (15 mg/kg), 6 times in total over a 15 day treatment period. We demonstrated that neither 5FU, nor 5FU combined with BGP-15, affected body composition indices, skeletal muscle mass or function. Adjuvant BGP-15 treatment did, however, prevent the 5FU-induced phosphorylation of p38 MAPK and p65 NF-B subunit, signalling pathways involved in cell stress and inflammatory signalling, respectively. This as associated with mitoprotection. 5FU reduced the expression of the key cytoskeletal proteins, desmin and dystrophin, which was not prevented by BGP-15. Combined, these data show that metronomic delivery of 5FU does not elicit physiological consequences to skeletal muscle mass and function but is implicit in priming skeletal muscle with a molecular signature for myopathy. BGP-15 has modest protective efficacy against the molecular changes induced by 5FU.

Genetic Disorders of Bone or Osteodystrophies of Jaws-A Review.

Bone is a specialized form of connective tissue, which is mineralized and made up of approximately 28% type I collagen and 5% noncollagenous matrix proteins. The properties of bone are very remarkable, because it is a dynamic tissue, undergoing constant renewal in response to mechanical, nutritional, and hormonal influences. In 1978, "The International Nomenclature of Constitutional Diseases of Bone" divided bone disorders into two broad groups: osteochondrodysplasias and dysostoses. The osteochondrodysplasia group is further subdivided into two categories: dysplasias (abnormalities of bone and/or cartilage growth) and osteodystrophies (abnormalities of bone and/or cartilage texture). The dysplasias form the largest group of bone disorders, hence the loose term "skeletal dysplasia" that is often incorrectly used when referring to a condition that is in reality an osteodystrophy or dysostosis. The word "dystrophy" implies any condition of abnormal development. "Osteodystrophies," as their name implies, are disturbances in the growth of bone. It is also known as osteodystrophia. It includes bone diseases that are neither inflammatory nor neoplastic but may be genetic, metabolic, or of unknown origin. Recent studies have shown that bone influences the activity of other organs, and the bone is also influenced by other organs and systems of the body, providing new insights and evidencing the complexity and dynamic nature of bone tissue. The 1,25-dihydroxyvitamin D3, or simply vitamin D, in association with other hormones and minerals, is responsible for mediating the intestinal absorption of calcium, which influences plasma calcium levels and bone metabolism. Diagnosis of the specific osteodystrophy type is a rather complex process and various biochemical markers and radiographic findings are used, so as to facilitate this condition. For diagnosis, we must consider the possibility of lesions related to bone metabolism altered by chronic renal failure (CRI), such as the different types of osteodystrophies, and differentiate from other possible neoplastic and/or inflammatory pathologies. It is important that the dentist must be aware of patients medical history, suffering from any systemic diseases, and identify the interference of the drugs and treatments to control them, so that we can able to perform the correct diagnosis and propose the most adequate treatment and outcomes of the individuals with bone lesions.

Grape-Leaf Extract Attenuates Alcohol-Induced Liver Injury via Interference with NF-κB Signaling Pathway.

Grape (Vitis vinifera) leaf extracts (GLEs) are known to be rich in phenolic compounds that exert potent antioxidant effects. Given the vulnerability of the liver to oxidative damage, antioxidants have been proposed as therapeutic agents and coadjuvant drugs to ameliorate liver pathologies. The current study was designed to characterize secondary metabolites and investigate the hepatoprotective effects of GLE and its underlying mechanisms. The secondary metabolites were profiled using HPLC-PDA-ESI-MS, and forty-five compounds were tentatively identified. In experimental in vivo design, liver injury was induced by oral administration of high doses of ethanol (EtOH) for 12 days to male Sprague Dawley rats that were split into five different groups. Blood samples and livers were then collected, and used for various biochemical, immunohistochemical, and histopathological analyses. Results showed that GLE-attenuated liver injury and promoted marked hepatic antioxidant effects, in addition to suppressing the increased heat-shock protein-70 expression. Moreover, GLE suppressed EtOH-induced expression of nuclear factor-κB (NF-B) p65 subunit and proinflammatory cytokine tumor necrosis factor-α. Caspase-3 and survivin were enhanced by EtOH intake and suppressed by GLE intake. Finally, EtOH-induced histopathological changes in liver sections were markedly normalized by GLE. In conclusion, our results suggested that GLE interferes with NF-B signaling and induces antioxidant effects, which both play a role in attenuating apoptosis and associated liver injury in a model of EtOH-induced liver damage in rats.

BGN/TLR4/NF-B Mediates Epigenetic Silencing of Immunosuppressive Siglec Ligands in Colon Cancer Cells.

Human Toll-like receptor (TLR) signaling plays a vital role in intestinal inflammation by activating the NF-B pathway. By querying GENT2 datasets, we identified the gene expression level of TLR2 and TLR4 as being substantially increased in colorectal cancer. Introduction of shRNAs for TLR4 but not TLR2 dramatically recovered disialyl Lewisa and sialyl 6-sulfo Lewisx glycans, which are preferentially expressed in non-malignant colonic epithelial cells and could serve as ligands for the immunosuppressive molecule Siglec-7. We screened several TLR4 ligands and found that among them BGN is highly expressed in cancers and is involved in the epigenetic silencing of Siglec-7 ligands. Suppression of BGN expression substantially downregulated NF-B activity and the marker H3K27me3 in the promoter regions of the SLC26A2 and ST6GalNAc6 genes, which are involved in the synthesis of those glycans, and restored expression of normal glycans as well as Siglec-7 binding activities. We show that in the presence of TLR4, inflammatory stimuli initiate a positive loop involving NF-B that activates BGN and further enhances TLR4 activity. Present findings indicate a putative mechanism for the promotion of carcinogenesis by loss of immunosuppressive ligands by the BGN/TLR4/ NF-B pathway.

Evidence That Calebin A, a Component of Curcuma Longa Suppresses NF-B Mediated Proliferation, Invasion and Metastasis of Human Colorectal Cancer Induced by TNF-ß (Lymphotoxin).

OBJECTIVE: Natural polyphenol Calebin A has been recently discovered as a novel derivate from turmeric with anti-cancer potential. Pro-inflammatory cytokine TNF-ß (lymphotoxin α) is a stimulant for cancer cell malignity via activation of NF-B pathway, also in colorectal cancer (CRC). Here, we investigated the potential of Calebin A to suppress TNF-ß-induced NF-B signalling in CRC. MATERIALS AND METHODS: Three distinct CRC cell lines (HCT116, RKO, SW480) were treated in monolayer or 3-dimensional alginate culture with TNF-ß, Calebin A, curcumin, BMS-345541, dithiothreitol (DTT) or antisense oligonucleotides-(ASO) against NF-B. RESULTS: Calebin A suppressed dose-dependent TNF-ß-induced CRC cell vitality and proliferation in monolayer culture. Further, in alginate culture, Calebin A significantly suppressed TNF-ß-enhanced colonosphere development, as well as invasion and colony formation of all three CRC cell lines investigated. Calebin A specifically blocked TNF-ß-induced activation and nuclear translocation of p65-NF-B, similar to curcumin (natural NF-B inhibitor), BMS-345541 (specific IKK inhibitor) and ASO-NF-B. Moreover, Immunofluorescence and Immunoblotting showed that Calebin A, similar to curcumin or BMS-345541 suppressed TNF-ß-induced activation and nuclear translocation of p65-NF-B and the transcription of NF-B-promoted biomarkers associated with proliferation, migration and apoptosis, in a dose- and time-dependent manner. Those findings were potentiated by the specific treatment of extracted nuclei with DTT, which abrogated Calebin A-mediated nuclear p65-NF-B-inhibition and restored p65-NF-B-activity in the nucleus. CONCLUSION: Overall, these results demonstrate, for the first time, that multitargeted Calebin A has an anti-cancer capability on TNF-ß-induced malignities through inhibitory targeting of NF-B activation in the cytoplasm, as well as by suppressing the binding of p65-NF-B to DNA.