Bioactive lipids in intervertebral disc degeneration and its therapeutic implications

Abstract Intervertebral disc (IVD) degeneration is not uncommon. It is estimated that approximately >60% of individuals above the age of 40 years suffer from IVD degeneration. Shan et al. showed that hyperglycemia can enhance apoptosis of anulus fibrosis cells in a JNK pathway and p38 mitogen-activated protein kinase (MAPK) pathway dependent fashion. Recent studies showed that IVD degeneration could be an inflammatory condition characterized by increased production of matrix metalloproteinases, TNF-α, nitric oxide, IL-6, IL-17, IL-9, and prostaglandin E2, and decreased formation of anti-inflammatory molecules such as lipoxin A4. This imbalance between pro- and anti-inflammatory molecules seem to activate JNK pathway and p38 MAPK pathway to induce apoptosis of anulus fibrosis and nucleus pulposus cells. The activation of production of PGE2 (due to activation of COX-2 pathway) seems to be dependent on p38/c-Fos and JNK/c-Jun activation in an AP-1-dependent manner. These results imply that suppressing pro-inflammatory events in the disc by either augmenting anti-inflammatory events or suppressing production of pro-inflammatory molecules or both may form a logical step in the prevention and management of IVD degeneration.

Download Full-text

Investigation of Antifungal Mechanisms of Thymol in the Human Fungal Pathogen, Cryptococcus neoformans

Molecules ◽

10.3390/molecules26113476 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3476

Author(s):

Kwang-Woo Jung ◽

Moon-Soo Chung ◽

Hyoung-Woo Bai ◽

Byung Yeoup Chung ◽

Sungbeom Lee

Keyword(s):

Cryptococcus Neoformans ◽

Fungal Pathogens ◽

Reverse Genetics ◽

Mapk Pathway ◽

Global Climate ◽

Mitogen Activated Protein Kinase ◽

Ergosterol Biosynthesis ◽

Thymus Vulgaris ◽

Dependent Manner ◽

Expression Levels

Due to lifespan extension and changes in global climate, the increase in mycoses caused by primary and opportunistic fungal pathogens is now a global concern. Despite increasing attention, limited options are available for the treatment of systematic and invasive mycoses, owing to the evolutionary similarity between humans and fungi. Although plants produce a diversity of chemicals to protect themselves from pathogens, the molecular targets and modes of action of these plant-derived chemicals have not been well characterized. Using a reverse genetics approach, the present study revealed that thymol, a monoterpene alcohol from Thymus vulgaris L., (Lamiaceae), exhibits antifungal activity against Cryptococcus neoformans by regulating multiple signaling pathways including calcineurin, unfolded protein response, and HOG (high-osmolarity glycerol) MAPK (mitogen-activated protein kinase) pathways. Thymol treatment reduced the intracellular concentration of Ca2+ by controlling the expression levels of calcium transporter genes in a calcineurin-dependent manner. We demonstrated that thymol decreased N-glycosylation by regulating the expression levels of genes involved in glycan-mediated post-translational modifications. Furthermore, thymol treatment reduced endogenous ergosterol content by decreasing the expression of ergosterol biosynthesis genes in a HOG MAPK pathway-dependent manner. Collectively, this study sheds light on the antifungal mechanisms of thymol against C. neoformans.

Download Full-text

Camel Milk Attenuates Rheumatoid Arthritis Via Inhibition of Mitogen Activated Protein Kinase Pathway

Cellular Physiology and Biochemistry ◽

10.1159/000480527 ◽

2017 ◽

Vol 43 (2) ◽

pp. 540-552 ◽

Cited By ~ 17

Author(s):

Hany H. Arab ◽

Samir A. Salama ◽

Tamer M. Abdelghany ◽

Hany A. Omar ◽

El-Shaimaa A. Arafa ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Mapk Pathway ◽

Lipid Peroxide ◽

Mitogen Activated Protein Kinase ◽

Camel Milk ◽

Tnf Α ◽

Mitogen Activated Protein ◽

Anti Oxidant ◽

Cox 2 ◽

Anti Inflammatory

Background/Aims: Camel milk (CM) has shown beneficial anti-inflammatory actions in several experimental and clinical settings. So far, its effect on rheumatoid arthritis (RA) has not been previously explored. Thus, the current work aimed to evaluate the effects of CM in Adjuvant-induced arthritis and air pouch edema models in rats, which mimic human RA. Methods: CM was administered at 10 ml/kg orally for 3 weeks starting on the day of Freund’s adjuvant paw inoculation. The levels of TNF-α and IL-10 were measured by ELISA while the protein expression of NF-κBp65, COX-2 and iNOS was detected by immunohistochemistry. The expression of MAPK target proteins was assessed by Western blotting. Results: CM attenuated paw edema, arthritic index and gait score along with dorsal pouch inflammatory cell migration. CM lowered the TNF-α and augmented the anti-inflammatory IL-10 levels in sera and exudates of arthritic rats. It also attenuated the expression of activated NF-κBp65, COX-2 and iNOS in the lining of the dorsal pouch. Notably, CM inhibited the MAPK pathway signal transduction via lowering the phosphorylation of p38 MAPK, ERK1/2 and JNK1/2 in rat hind paws. Additionally, CM administration lowered the lipid peroxide and nitric oxide levels and boosted glutathione and total anti-oxidant capacity in sera and exudates of animals. Conclusion: The observed CM downregulation of the arthritic process may support the interest of CM consumption as an adjunct approach for the management of RA.

Download Full-text

(E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) Phenol Ameliorates MPTP-Induced Dopaminergic Neurodegeneration by Inhibiting the STAT3 Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms20112632 ◽

2019 ◽

Vol 20 (11) ◽

pp. 2632 ◽

Cited By ~ 1

Author(s):

Ji Yeon Choi ◽

Jaesuk Yun ◽

Chul Ju Hwang ◽

Hee Pom Lee ◽

Hae Deun Kim ◽

...

Keyword(s):

Calcium Binding ◽

Cultured Cells ◽

Mapk Pathway ◽

Inflammatory Marker ◽

Mitogen Activated Protein Kinase ◽

Dopamine Depletion ◽

Behavioral Impairment ◽

Mao B ◽

Dopaminergic Neurodegeneration ◽

Anti Inflammatory

Neuroinflammation is implicated in dopaminergic neurodegeneration. We have previously demonstrated that (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP), a selective signal transducer and activator of transcription 3 (STAT3) inhibitor, has anti-inflammatory properties in several inflammatory disease models. We investigated whether MMPP could protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic cell loss and behavioral impairment. Imprinting control region (ICR) mice (8 weeks old, n = 10 per group) were administered MMPP (5 mg/kg) in drinking water for 1 month, and injected with MPTP (15 mg/kg, four times with 2 h intervals) during the last 7 days of treatment. MMPP decreased MPTP-induced behavioral impairments in rotarod, pole, and gait tests. We also showed that MMPP ameliorated dopamine depletion in the striatum and inflammatory marker elevation in primary cultured neurons by high-performance liquid chromatography and immunohistochemical analysis. Increased activation of STAT3, p38, and monoamine oxidase B (MAO-B) were observed in the substantia nigra and striatum after MPTP injection, effects that were attenuated by MMPP treatment. Furthermore, MMPP inhibited STAT3 activity and expression of neuroinflammatory proteins, including ionized calcium binding adaptor molecule 1 (Iba1), inducible nitric oxide synthase (iNOS), and glial fibrillary acidic protein (GFAP) in 1-methyl-4-phenylpyridinium (MPP+; 0.5 mM)-treated primary cultured cells. However, mitogen-activated protein kinase (MAPK) inhibitors augmented the activity of MMPP. Collectively, our results suggest that MMPP may be an anti-inflammatory agent that attenuates dopaminergic neurodegeneration and neuroinflammation through MAO-B and MAPK pathway-dependent inhibition of STAT3 activation.

Download Full-text

Higenamine inhibits IL-1β-induced inflammation in human nucleus pulposus cells

Bioscience Reports ◽

10.1042/bsr20190857 ◽

2019 ◽

Vol 39 (6) ◽

Cited By ~ 2

Author(s):

Xiaoliang Bai ◽

Wenyuan Ding ◽

Sidong Yang ◽

Xiaohui Guo

Keyword(s):

Nitric Oxide ◽

Signaling Pathway ◽

Nucleus Pulposus ◽

Inflammatory Activity ◽

Nucleus Pulposus Cells ◽

Necrosis Factor Alpha ◽

Natural Progression ◽

Anti Inflammatory ◽

Inflammatory Molecules ◽

Oxide Synthase

Abstract Intervertebral disc degeneration (IDD) is a natural progression of the aging process associated with inflammation. Higenamine, a plant-based alkaloid, has been identified to possess various pharmacological properties, including anti-inflammatory activity. In the present study, we aimed to evaluate the role of higenamine in interleukin (IL)-1β-induced inflammation in human nucleus pulposus cells (NPCs). The results showed that higenamine improved cell viability in IL-1β-induced NPCs. The IL-1β-dependent up-regulation of inflammatory molecules including inducible nitric oxide synthase (iNOS), nitric oxide (NO), prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), tumor necrosis factor alpha (TNF-α), and IL-6 was attenuated by higenamine in NPCs. The increased productions of matrix metalloproteinases (MMP-3 and MMP-13), as well as a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS-4 and ADAMTS-5) were significantly mitigated by higenamine treatment. Furthermore, we also found that higenamine suppressed the IL-1β-induced activation of NF-κB signaling pathway in NPCs. In conclusion, the present study proved that higenamine exhibited anti-inflammatory activity against IL-1β-induced inflammation in NPCs via inhibiting NF-κB signaling pathway. These results suggested that higenamine might be a therapeutic agent for the treatment of IDD.

Download Full-text

Phosphorylation of High-Mobility Group Protein A2 by Nek2 Kinase during the First Meiotic Division in Mouse Spermatocytes

Molecular Biology of the Cell ◽

10.1091/mbc.e03-09-0638 ◽

2004 ◽

Vol 15 (3) ◽

pp. 1224-1232 ◽

Cited By ~ 55

Author(s):

Silvia Di Agostino ◽

Monica Fedele ◽

Paolo Chieffi ◽

Alfredo Fusco ◽

Pellegrino Rossi ◽

...

Keyword(s):

Mapk Pathway ◽

Chromatin Condensation ◽

High Mobility ◽

Mitogen Activated Protein Kinase ◽

Dependent Manner ◽

Correct Process ◽

High Mobility Group Protein ◽

Mitogen Activated Protein ◽

Pachytene Spermatocytes

The mitogen-activated protein kinase (MAPK) pathway is required for maintaining the chromatin condensed during the two meiotic divisions and to avoid a second round of DNA duplication. However, molecular targets of the MAPK pathway on chromatin have not yet been identified. Here, we show that the architectural chromatin protein HMGA2 is highly expressed in male meiotic cells. Furthermore, Nek2, a serine-threonine kinase activated by the MAPK pathway in mouse pachytene spermatocytes, directly interacts with HMGA2 in vitro and in mouse spermatocytes. The interaction does not depend on the activity of Nek2 and seems constitutive. On progression from pachytene to metaphase, Nek2 is activated and HMGA2 is phosphorylated in an MAPK-dependent manner. We also show that Nek2 phosphorylates in vitro HMGA2 and that this phosphorylation decreases the affinity of HMGA2 for DNA and might favor its release from the chromatin. Indeed, we find that most HMGA2 associates with chromatin in mouse pachytene spermatocytes, whereas it is excluded from the chromatin upon the G2/M progression. Because hmga2-/- mice are sterile and show a dramatic impairment of spermatogenesis, it is possible that the functional interaction between HMGA2 and Nek2 plays a crucial role in the correct process of chromatin condensation in meiosis.

Download Full-text

Angiotensin II-Induced Mitogen-Activated Protein Kinase Phosphatase-1 Expression in Bovine Adrenal Glomerulosa Cells: Implications in Mineralocorticoid Biosynthesis

Endocrinology ◽

10.1210/en.2007-0241 ◽

2007 ◽

Vol 148 (11) ◽

pp. 5573-5581 ◽

Cited By ~ 10

Author(s):

Andrés J. Casal ◽

Stéphane Ryser ◽

Alessandro M. Capponi ◽

Carine F. Wang-Buholzer

Keyword(s):

Angiotensin Ii ◽

Mapk Pathway ◽

Fold Increase ◽

Zona Glomerulosa ◽

Mitogen Activated Protein Kinase ◽

Receptor Subtype ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Aldosterone Production ◽

Glomerulosa Cells

Angiotensin II (AngII) stimulates aldosterone biosynthesis in the zona glomerulosa of the adrenal cortex. AngII also triggers the MAPK pathways (ERK1/2 and p38). Because ERK1/2 phosphorylation is a transient process, phosphatases could play a crucial role in the acute steroidogenic response. Here we show that the dual specificity (threonine/tyrosine) MAPK phosphatase-1 (MKP-1) is present in bovine adrenal glomerulosa cells in primary culture and that AngII markedly increases its expression in a time- and concentration-dependent manner (IC50 = 1 nm), a maximum of 548 ± 10% of controls being reached with 10 nm AngII after 3 h (n = 3, P < 0.01). This effect is completely abolished by losartan, a blocker of the AT1 receptor subtype. Moreover, this AngII-induced MKP-1 expression is reduced to 250 ± 35% of controls (n = 3, P < 0.01) in the presence of U0126, an inhibitor of ERK1/2 phosphorylation, suggesting an involvement of the ERK1/2 MAPK pathway in MKP-1 induction. Indeed, shortly after AngII-induced phosphorylation of ERK1/2 (220% of controls at 30 min), MKP-1 protein expression starts to increase. This increase is associated with a reduction in ERK1/2 phosphorylation, which returns to control values after 3 h of AngII challenge. Enhanced MKP-1 expression is essentially due to a stabilization of MKP-1 mRNA. AngII treatment leads to a 53-fold increase in phosphorylated MKP-1 levels and a doubling of MKP-1 phosphatase activity. Overexpression of MKP-1 results in decreased phosphorylation of ERK1/2 and aldosterone production in response to AngII stimulation. These results strongly suggest that MKP-1 is the specific phosphatase induced by AngII and involved in the negative feedback mechanism ensuring adequate ERK1/2-mediated aldosterone production in response to the hormone.

Download Full-text

Flavonoid Naringenin: A Potential Immunomodulator forChlamydia trachomatisInflammation

Mediators of Inflammation ◽

10.1155/2013/102457 ◽

2013 ◽

Vol 2013 ◽

pp. 1-13 ◽

Cited By ~ 37

Author(s):

Abebayehu N. Yilma ◽

Shree R. Singh ◽

Lisa Morici ◽

Vida A. Dennis

Keyword(s):

Inflammatory Mediators ◽

Mapk Pathway ◽

Costimulatory Molecule ◽

Asymptomatic Infection ◽

Mitogen Activated Protein Kinase ◽

Gene Transcript ◽

Dependent Manner ◽

Sexually Transmitted ◽

Gm Csf ◽

Mitogen Activated Protein

Chlamydia trachomatis, the agent of bacterial sexually transmitted infections, can manifest itself as either acute cervicitis, pelvic inflammatory disease, or a chronic asymptomatic infection. Inflammation induced byC. trachomatiscontributes greatly to the pathogenesis of disease. Here we evaluated the anti-inflammatory capacity of naringenin, a polyphenolic compound, to modulate inflammatory mediators produced by mouse J774 macrophages infected with liveC. trachomatis. Infected macrophages produced a broad spectrum of inflammatory cytokines (GM-CSF, TNF, IL-1β, IL-1α, IL-6, IL-12p70, and IL-10) and chemokines (CCL4, CCL5, CXCL1, CXCL5, and CXCL10) which were downregulated by naringenin in a dose-dependent manner. Enhanced protein and mRNA gene transcript expressions of TLR2 and TLR4 in addition to the CD86 costimulatory molecule on infected macrophages were modulated by naringenin. Pathway-specific inhibition studies disclosed that p38 mitogen-activated-protein kinase (MAPK) is involved in the production of inflammatory mediators by infected macrophages. Notably, naringenin inhibited the ability ofC. trachomatisto phosphorylate p38 in macrophages, suggesting a potential mechanism of its attenuation of concomitantly produced inflammatory mediators. Our data demonstrates that naringenin is an immunomodulator of inflammation triggered byC. trachomatis, which possibly may be mediated upstream by modulation of TLR2, TLR4, and CD86 receptors on infected macrophages and downstream via the p38 MAPK pathway.

Download Full-text

LRP5-deficiency in OsxCreERT2 mice models intervertebral disc degeneration by aging and compression

10.1101/720656 ◽

2019 ◽

Author(s):

Matthew J. Silva ◽

Nilsson Holguin

Keyword(s):

Transcription Factor ◽

Intervertebral Disc ◽

Wnt Signaling ◽

Cell Fate ◽

Biomechanical Properties ◽

Nucleus Pulposus Cells ◽

Hypertrophic Chondrocyte ◽

Age Related ◽

Ivd Degeneration

ABSTRACTOsterix is a critical transcription factor of mesenchymal stem cell fate, where its loss or loss of WNT signaling diverts differentiation to a chondrocytic lineage. Intervertebral disc (IVD) degeneration activates differentiation of prehypertrophic chondrocyte-like cells and inactivates WNT signaling, but its interacting role with osterix is unclear. First, compared to young-adult (5mo), mechanical compression of old (18mo) IVD induced greater IVD degeneration. Aging (5 vs 12mo) and/or compression reduced the transcription of osterix and notochordal marker T by 40-75%. Compression elevated transcription of hypertrophic chondrocyte marker MMP13 and pre-osterix transcription factor RUNX2, but less so in 12mo IVD. Next, using an Ai9/td reporter and immunohistochemistry, annulus fibrosus and nucleus pulposus cells of 5mo IVD expressed osterix, but aging and compression reduced its expression. Lastly, in vivo LRP5-deficiency in osterix-expressing cells degenerated the IVD, inactivated WNT signaling, reduced the biomechanical properties by 45-70%, and reduced transcription of osterix, notochordal markers and chondrocytic markers by 60-80%. Overall, these data indicate that age-related inactivation of WNT signaling in osterix-expressing cells may limit regeneration by depleting progenitors and attenuating the expansion of chondrocyte-like cells.

Download Full-text

The REDD1/TXNIP Complex Accelerates Oxidative Stress-Induced Apoptosis of Nucleus Pulposus Cells through the Mitochondrial Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/7397516 ◽

2021 ◽

Vol 2021 ◽

pp. 1-22

Author(s):

Huipeng Yin ◽

Kun Wang ◽

Abhirup Das ◽

Gaocai Li ◽

Yu Song ◽

...

Keyword(s):

Oxidative Stress ◽

Intervertebral Disc ◽

Nucleus Pulposus ◽

Cell Apoptosis ◽

Redox Homeostasis ◽

Mitochondrial Pathway ◽

Nucleus Pulposus Cells ◽

Damage Response ◽

Induced Apoptosis ◽

Ivd Degeneration

The death of nucleus pulposus (NP) cells is an important cause of intervertebral disc (IVD) degeneration. Redox disturbance caused by dysfunctional mitochondria has been considered as a vital risk for NP cell survival. It is valuable to identify key proteins maintaining mitochondrial function in NP cells. A previous study found that regulated in development and DNA damage response 1 (REDD1) are upregulated during intervertebral disc degeneration and that REDD1 can cause NP cell apoptosis. Thus, the present study further explores the effect of REDD1 on IVD degeneration. Our results showed that REDD1 promotes NP cell apoptosis via the mitochondrial pathway. Importantly, REDD1 formed a complex with TXNIP to strengthen its own action, and the combination was consolidated under H2O2-induced oxidative stress. The combined inhibition of the REDD1/TXNIP complex was better than that of REDD1 or TXNIP alone in restoring cell proliferation and accelerating apoptosis. Moreover, p53 acts as the transcription factor of REDD1 to regulate the REDD1/TXNIP complex under oxidative stress. Altogether, our results demonstrated that the REDD1/TXNIP complex mediated H2O2-induced human NP cell apoptosis and IVD degeneration through the mitochondrial pathway. Interferences on these sites to achieve mitochondrial redox homeostasis may be a novel therapeutic strategy for oxidative stress-associated IVD degeneration.

Download Full-text

Propionibacterium acnes Accelerates Intervertebral Disc Degeneration by Inducing Pyroptosis of Nucleus Pulposus Cells via the ROS-NLRP3 Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/4657014 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Guoqing Tang ◽

Xiaoguang Han ◽

Zhijie Lin ◽

Hongbin Qian ◽

Bing Chen ◽

...

Keyword(s):

Nucleus Pulposus ◽

Propionibacterium Acnes ◽

Strong Association ◽

Intervertebral Discs ◽

Inflammatory Factors ◽

Death Process ◽

Dependent Manner ◽

Nucleus Pulposus Cells ◽

Alternative Treatment Strategy ◽

Ivd Degeneration

Our previous study verified the occurrence of Propionibacterium acnes (P. acnes), a low-virulence anaerobic bacterium, latently residing in degenerated intervertebral discs (IVDs), and the infection had a strong association with IVD degeneration. We explored whether P. acnes induces nucleus pulposus cell (NPC) pyroptosis, a more dangerous cell death process than apoptosis, and accelerates IVD degeneration via the pyroptotic products interleukin- (IL-) 1β and IL-18. After coculturing with P. acnes, human NPCs showed significant upregulation of NOD-like receptor 3 (NLRP3), cleaved IL-1β, cleaved caspase-1, and cleaved gasdermin D in response to the overexpression of IL-1β and IL-18 in a time- and dose-dependent manner. In addition, the gene expression of inflammatory factors and catabolic enzymes significantly increased in normal NPCs when cocultured with pyroptotic NPCs in a transwell system, and the adverse effects were inhibited when NPC pyroptosis was suppressed. Furthermore, inoculation of P. acnes into the IVDs of rats caused significant pyroptosis of NPCs and remarkable IVD degeneration. Finally, coculture of NPCs with P. acnes induced the overexpression of reactive oxygen species (ROS) and NLRP3, while inhibition of both factors reduced NPC pyroptosis. Therefore, P. acnes induces NPC pyroptosis via the ROS-NLRP3 signaling pathway, and the pyroptotic NPCs cause an IVD degeneration cascade. Targeting the P. acnes-induced pyroptosis of NPCs may become an alternative treatment strategy for IVD degeneration in the future.

Download Full-text