ABSTRACT
Purpose: The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, crucial in infectious and inflammatory diseases by regulating IL-1ß, presents a target for disease management. Neisseria gonorrhoeae causes gonorrhea in over 87 million people annually, with previous research revealing NLRP3 inflammasome activation in infected macrophages. No natural products have been reported to counteract this activation. Exploring honokiol, a phenolic compound from Chinese herbal medicine, we investigated its impact on NLRP3 inflammasome activation in N. gonorrhoeae-infected macrophages. Methods: Honokiol's impact on the protein expression of pro-inflammatory mediators was analyzed using ELISA and Western blotting. The generation of intracellular H2O2 and mitochondrial reactive oxygen species (ROS) was detected through specific fluorescent probes (CM-H2DCFDA and MitoSOX, respectively) and analyzed by flow cytometry. Mitochondrial membrane integrity was assessed using specific fluorescent probes (MitoTracker and DiOC2(3)) and analyzed by flow cytometry. Additionally, the effect of honokiol on the viability of N. gonorrhoeae was examined through an in vitro colony-forming units assay. Results: Honokiol effectively inhibits caspase-1, caspase-11 and GSDMD activation and reduces the extracellular release of IL-1ß, NLRP3, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) in N. gonorrhoeae-infected macrophages. Detailed investigations have demonstrated that honokiol lowers the production of H2O2 and the phosphorylation of ERK1/2 in N. gonorrhoeae-infected macrophages. Importantly, the phosphorylation of JNK1/2 and p38 and the activation of NF-κB remain unaffected. Moreover, honokiol reduces the N. gonorrhoeae-mediated generation of reactive oxygen species within the mitochondria, preserving their integrity. Additionally, honokiol suppresses the expression of the pro-inflammatory mediator IL-6 and inducible nitric oxide synthase induced by N. gonorrhoeae independently of NLRP3. Impressively, honokiol exhibits in vitro anti-gonococcal activity against N. gonorrhoeae. Conclusion: Honokiol inhibits the NLRP3 inflammasome in N. gonorrhoeae-infected macrophages and holds great promise for further development as an active ingredient in the prevention and treatment of symptoms associated with gonorrhea.
ABSTRACT
Inflammatory bowel disease (IBD) comprises a group of idiopathic intestinal disorders, including ulcerative colitis and Crohn's disease, significantly impacting the quality of life for affected individuals. The effective management of these conditions remains a persistent challenge. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, a complex molecular structure, regulates the production of pro-inflammatory cytokines such as interleukin-1ß. Abnormal activation of the NLRP3 inflammasome plays a pivotal role in the development of IBD, making it a compelling target for therapeutic intervention. Our research revealed that cinnamaldehyde (CA), a major bioactive compound found in the leaves of Cinnamomum osmophloeum kaneh, demonstrated a remarkable ability to alleviate colitis induced by dextran sulfate sodium (DSS) in a mouse model. This effect was attributed to CA's ability to downregulate the activation of the NLRP3 inflammasome and reduce the expression of pro-inflammatory mediators in the colon. In the mechanism study, we observed that CA inhibited the NLRP3 inflammasome in macrophages, at least partially, by enhancing the autophagic response, without reducing mitochondrial damage. These findings collectively suggest that CA holds significant potential as a therapeutic agent for enhancing the management of IBD, offering a promising avenue for further research and development.
Subject(s)
Acrolein , Cinnamomum , Colitis , Dextran Sulfate , Inflammasomes , Mice, Inbred C57BL , NLR Family, Pyrin Domain-Containing 3 Protein , Plant Leaves , Animals , Acrolein/analogs & derivatives , Acrolein/pharmacology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , Mice , Colitis/chemically induced , Colitis/drug therapy , Cinnamomum/chemistry , Inflammasomes/drug effects , Inflammasomes/metabolism , Plant Leaves/chemistry , MaleABSTRACT
BACKGROUND: Worldwide, more than 125 million people are infected with Shigella each year and develop shigellosis. In our previous study, we provided evidence that Shigella sonnei infection triggers activation of the NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome in macrophages. NLRP3 inflammasome is responsible for regulating the release of the proinflammatory cytokines interleukin (IL)-1ß and IL-18 through the protease caspase-1. Researchers and biotech companies have shown great interest in developing inhibitors of the NLRP3 inflammasome, recognizing it as a promising therapeutic target for several diseases. The leaves of Cinnamomum osmophloeum kaneh, an indigenous tree species in Taiwan, are rich in cinnamaldehyde (CA), a compound present in significant amounts. Our aim is to investigate how CA affects the activation of the NLRP3 inflammasome in S. sonnei-infected macrophages. METHODS: Macrophages were infected with S. sonnei, with or without CA. ELISA and Western blotting were employed to detect protein expression or phosphorylation levels. Flow cytometry was utilized to assess H2O2 production and mitochondrial damage. Fluorescent microscopy was used to detect cathepsin B activity and mitochondrial ROS production. Additionally, colony-forming units were employed to measure macrophage phagocytosis and bactericidal activity. RESULTS: CA inhibited the NLRP3 inflammasome in S. sonnei-infected macrophages by suppressing caspase-1 activation and reducing IL-1ß and IL-18 expression. CA also inhibited pyroptosis by decreasing caspase-11 and Gasdermin D activation. Mechanistically, CA reduced lysosomal damage and enhanced autophagy, while leaving mitochondrial damage, mitogen-activated protein kinase phosphorylation, and NF-κB activation unaffected. Furthermore, CA significantly boosted phagocytosis and the bactericidal activity of macrophages against S. sonnei, while reducing secretion of IL-6 and tumour necrosis factor following infection. CONCLUSION: CA shows promise as a nutraceutical for mitigating S. sonnei infection by diminishing inflammation and enhancing phagocytosis and the bactericidal activity of macrophages against S. sonnei.
ABSTRACT
The intracellular sensor protein complex known as the NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome plays a crucial role in regulating inflammatory diseases by overseeing the production of interleukin (IL)-1ß and IL-18. Targeting its abnormal activation with drugs holds significant promise for inflammation treatment. This study highlights LCZ696, an angiotensin receptor-neprilysin inhibitor, as an effective suppressor of NLRP3 inflammasome activation in macrophages stimulated by ATP, nigericin, and monosodium urate. LCZ696 also reduces caspase-11 and GSDMD activation, lactate dehydrogenase release, propidium iodide uptake, and the extracellular release of NLRP3 and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) in ATP-activated macrophages, suggesting a potential mitigation of pyroptosis. Mechanistically, LCZ696 lowers mitochondrial reactive oxygen species and preserves mitochondrial integrity. Importantly, it does not significantly impact NLRP3, proIL-1ß, inducible nitric oxide synthase, cyclooxygenase-2 expression, or NF-κB activation in lipopolysaccharide-activated macrophages. LCZ696 partially inhibits the NLRP3 inflammasome through the induction of autophagy. In an in vivo context, LCZ696 alleviates NLRP3-associated colitis in a mouse model by reducing colonic expression of IL-1ß and tumor necrosis factor-α. Collectively, these findings suggest that LCZ696 holds significant promise as a therapeutic agent for ameliorating NLRP3 inflammasome activation in various inflammatory diseases, extending beyond its established use in hypertension and heart failure treatment.
Subject(s)
Aminobutyrates , Biphenyl Compounds , Colitis , Dextran Sulfate , Disease Models, Animal , Inflammasomes , Macrophages , Mitochondria , NLR Family, Pyrin Domain-Containing 3 Protein , Valsartan , Animals , Mice , Aminobutyrates/pharmacology , Aminobutyrates/therapeutic use , Angiotensin Receptor Antagonists/pharmacology , Angiotensin Receptor Antagonists/therapeutic use , Biphenyl Compounds/pharmacology , Colitis/drug therapy , Colitis/chemically induced , Colitis/metabolism , Dextran Sulfate/toxicity , Drug Combinations , Inflammasomes/metabolism , Inflammasomes/antagonists & inhibitors , Macrophages/metabolism , Macrophages/drug effects , Mice, Inbred C57BL , Mitochondria/drug effects , Mitochondria/metabolism , Neprilysin/antagonists & inhibitors , Neprilysin/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , Valsartan/pharmacology , MaleABSTRACT
Purpose: Intervertebral disc (IVD) degeneration, associated with aging, may cause low back pain and disability, with obesity as a significant risk factor. In a prior study, we found a positive correlation between IVD degeneration and levels of matrix metalloproteinase-1 (MMP-1) and leptin. Yet, the interaction between MMP-1 and leptin in IVD degeneration is unclear. Our research seeks to explore leptin's influence on MMP-1 expression and the underlying mechanisms in human intervertebral disc cartilage endplate-derived stem cells, specifically SV40 cells. Methods: The mRNA and protein expression in leptin-stimulated SV40 cells were assessed using RT-real-time PCR and Western blotting or ELISA, respectively. We examined leptin-mediated RhoA activation through a GTP-bound RhoA pull-down assay. Furthermore, the phosphorylation levels of mitogen-activated protein kinases and AKT in leptin-stimulated SV40 cells were analyzed using Western blotting. The activation of NF-κB by leptin was investigated by assessing phosphorylation of IKKα/ß, IκBα, and NF-κB p65, along with the nuclear translocation of NF-κB p65. To understand the underlying mechanism behind leptin-mediated MMP-1 expression, we employed specific inhibitors. Results: Leptin triggered the mRNA and protein expression of MMP-1 in SV40 cells. In-depth mechanistic investigations uncovered that leptin heightened RhoA activity, promoted ERK1/2 phosphorylation, and increased NF-κB activity. However, leptin did not induce phosphorylation of JNK1/2, p38, or AKT. When we inhibited RhoA, ERK1/2, and NF-κB, it resulted in a decrease in MMP-1 expression. Conversely, inhibition of reactive oxygen species and NADPH oxidase did not yield the same outcome. Additionally, inhibiting RhoA or ERK1/2 led to a reduction in leptin-induced NF-κB activation. Moreover, inhibiting RhoA also decreased leptin-mediated ERK1/2 phosphorylation. Conclusion: These results indicated that leptin induced MMP-1 expression in SV40 cells through the RhoA/ERK1/2/NF-κB axis. This study provided the pathogenic role of leptin and suggested the potential therapeutic target for IVD degeneration.
ABSTRACT
Inflammatory bowel disease (IBD) is a non-infectious disease characterized by chronic inflammation of the gastrointestinal tract. Currently, management of IBD is still a clinical challenge. The purpose of this study was to investigate the therapeutic potential of surfactin containing Bacillus licheniformis-fermented products (SBLF) and commercial surfactin (CS) on the treatment of dextran sulfate sodium (DSS)-induced colitis in a mouse model. We found that mice that received drinking water containing 3% DSS developed significant colitis symptoms, including increased disease activity index, body weight loss, shortening of the colon length, splenomegaly, colonic inflammation and colonic NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation. Notably, orally received SBLF, CS or clinical anti-inflammatory drug 5-aminosalicylic acid improved DSS-induced colitis symptoms in mice. These findings show that SBLF can improve IBD in mice by reducing colonic inflammation and inhibiting the NLRP3 inflammasome activation, suggesting that SBLF has the potential to be used as a nutraceutical in humans or a feed additive in economic and companion animals for preventing IBD.
ABSTRACT
Intervertebral disc degeneration (IVDD), for which obesity and genetics are known risk factors, is a chronic process that alters the structure and function of the intervertebral discs (IVD). Circulating leptin is positively correlated with body weight and is often measured to elucidate the pathogenesis of IVD degeneration. In this study, we examined the associations of LEP single nucleotide polymorphisms (SNPs) genetic and environmental effects with IVDD. A total of 303 Taiwanese patients with IVDD (mean age, 58.6 ± 12.7 years) undergoing cervical discectomy for neck pain or lumbar discectomy for back pain were enrolled. Commercially available enzyme-linked immunosorbent assay (ELISA) kits measured the circulating plasma leptin levels. TaqMan SNP genotyping assays genotyped the LEP SNPs rs2167270 and rs7799039. Leptin levels were significantly increased in obese individuals (p < 0.001) and non-obese or obese women (p < 0.001). In the dominant model, recoded minor alleles of rs2167270 and rs7799039 were associated with higher leptin levels in all individuals (p = 0.011, p = 0.012). Further, the association between these LEP SNPs and leptin levels was significant only in obese women (p = 0.025 and p = 0.008, respectively). There was an interaction effect between sex and obesity, particularly among obese women (interaction p = 0.04 and 0.02, respectively). Our findings demonstrate that these SNPs have sex-specific associations with BMI in IVDD patients, and that obesity and sex, particularly among obese women, may modify the LEP transcription effect.
Subject(s)
Intervertebral Disc Degeneration , Leptin , Male , Humans , Female , Middle Aged , Aged , Leptin/genetics , Intervertebral Disc Degeneration/genetics , Intervertebral Disc Degeneration/complications , Obesity/genetics , Obesity/complications , Receptors, Leptin/genetics , Polymorphism, Single NucleotideABSTRACT
The intracellular sensor NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome controls caspase-1 activity and the maturation and release of the cytokines interleukin (IL)-1ß and IL-18. The NLRP3 inflammasome has attracted the attention of the pharmaceutical industry because it promotes the pathogenesis of many diseases, making it a promising target for drug development. Litsea cubeba (Lour.) is a plant traditionally used as a seasoning in Taiwan and in other Asian countries. In this study, we investigated the inhibitory activity of the leaves of L. cubeba against the NLRP3 inflammasome. We found that the ethanol extract of L. cubeba leaves (MLE) inhibited the NLRP3 inflammasome in macrophages by reducing caspase-1 activation and IL-1ß secretion. MLE reduced pyroptosis in macrophages and inhibited the release of NLRP3 and apoptosis-associated speck-like protein containing a CARD (ASC). In a mechanistic study, MLE reduced mitochondrial reactive oxygen species (ROS) production and preserved mitochondrial integrity, which led to reduced mitochondrial DNA release into the cytosol. MLE did not reduce the expression levels of NLRP3, IL-1ß precursor or TNF-α in lipopolysaccharide (LPS)-activated macrophages. These results indicated that MLE inhibited the NLRP3 inflammasome by suppressing the activation signals of the NLRP3 inflammasome but not by reducing the priming signal induced by LPS. In addition, oral administration of MLE (20-80 mg/kg) ameliorated dextran sulfate sodium (DSS)-induced colitis in a mouse model. Notably, mice that received MLE (1 and 2 g/kg) daily for 7 days did not exhibit visible side effects. Gas chromatography-mass spectrometry (GC-MS) analysis found that α-Terpinyl acetate (27.2%) and 1,8-Cineole (17.7%) were the major compounds in MLE. These results indicated that L. cubeba leaves have the potential to be a nutraceutical for preventing and improving NLRP3 inflammasome-related diseases.
ABSTRACT
Aberrant activation of the NLRP3 inflammasome promotes the pathogenesis of many inflammatory diseases. The development of the NLRP3 inflammasome inhibitors from existing drugs for new therapeutic purposes is becoming more important. Candesartan is an angiotensin II receptor antagonist widely used as a blood pressure-lowering drug; however, the inhibitory potential of candesartan on the NLRP3 inflammasome has not yet been investigated. We demonstrated that candesartan significantly inhibited the NLRP3 inflammasome and pyroptosis in macrophages. Mechanistic analysis revealed that candesartan inhibited the expression of NLRP3 and proIL-1ß by suppressing NF-κB activation and reducing the phosphorylation of ERK1/2 and JNK1/2. Candesartan reduced mitochondrial damage and inhibited the NLRP3 inflammasome assembly by suppressing NLRP3 binding to PKR, NEK7 and ASC. In addition, candesartan inhibited IL-1ß secretion partially through autophagy induction. Furthermore, oral administration of candesartan reduced peritoneal neutrophil influx, NLRP3 and ASC expression in peritoneal cells, and lavage fluid concentrations of active caspase-1, IL-1ß, IL-6 and MCP-1 in uric acid crystal-injected mice. These results indicated that candesartan has board anti-inflammatory effects and has the potential to be repositioned to ameliorate inflammatory diseases or NLRP3-associated complications.
Subject(s)
Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Angiotensin Receptor Antagonists , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Benzimidazoles , Biphenyl Compounds , Drug Repositioning , Inflammasomes/metabolism , Mice , Mice, Inbred C57BL , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , TetrazolesABSTRACT
(1) Background: We investigated the association of four immune-inflammatory markers with clinical features and established location-specific nomograms to predict mortality risk in patients with intracerebral hemorrhage (ICH). (2) Methods: We retrospectively enrolled 613 inpatients with acute ICH. (3) Results: Overall mortality was 22%, which was highest in pontine hemorrhage and lowest in thalamic hemorrhage. All four immune-inflammatory markers exhibited a positive linear correlation with glucose, ICH volume, ICH score, and discharge Modified Rankin Scale (mRS) score. Significant predictors of death due to lobar/putaminal hemorrhage were age, glucose and creatinine levels, initial Glasgow Coma Scale (GCS) score, ICH volume, and presence of intraventricular hemorrhage. None of the immune-inflammatory markers were significant predictors of unfavorable outcome or death. We selected significant factors to establish nomograms for predicting death due to lobar/putaminal, thalamic, pontine, and cerebellar hemorrhages. The C-statistic for predicting death in model I (comprising factors in the establishment of the nomogram) in each type of ICH was higher than that in model II (comprising ICH score alone), except for cerebellar hemorrhage. These nomograms for predicting death had good discrimination (C-index: 0.889 to 0.975) and prediction probabilities (C-index: 0.890 to 0.965). (4) Conclusions: Higher immune-inflammatory markers were associated with larger ICH volume, worse initial GCS, and unfavorable outcomes, but were not independent prognostic predictors. The location-specific nomograms provided novel and accurate models for predicting mortality risk.
ABSTRACT
BACKGROUND: Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of the CAG repeat in the huntingtin (HTT) gene. When the number of CAG repeats exceeds 36, the translated expanded polyglutamine-containing HTT protein (mutant HTT [mHTT]) interferes with the normal functions of many cellular proteins and subsequently jeopardizes important cellular machineries in major types of brain cells, including neurons, astrocytes, and microglia. The NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome, which comprises NLRP3, ASC, and caspase-1, is involved in the activation of IL-1ß and IL-18 and has been implicated in various biological functions. Although the existence of the NLRP3 inflammasome in the brain has been documented, the roles of the NLRP3 inflammasome in HD remain largely uncharacterized. MCC950 is a highly selective and potent small-molecule inhibitor of NLRP3 that has been used for the treatment of several diseases such as Alzheimer's disease. However, whether MCC950 is also beneficial in HD remains unknown. Therefore, we hypothesized that MCC950 exerts beneficial effects in a transgenic mouse model of HD. METHODS: To evaluate the effects of MCC950 in HD, we used the R6/2 (B6CBA-Tg[HDexon1]62Gpb/1J) transgenic mouse model of HD, which expresses exon 1 of the human HTT gene carrying 120 ± 5 CAG repeats. Male transgenic R6/2 mice were treated daily with MCC950 (10 mg/kg of body weight; oral administration) or water for 5 weeks from the age of 7 weeks. We examined neuronal density, neuroinflammation, and mHTT aggregation in the striatum of R6/2 mice vs. their wild-type littermates. We also evaluated the motor function, body weight, and lifespan of R6/2 mice. RESULTS: Systematic administration of MCC950 to R6/2 mice suppressed the NLRP3 inflammasome, decreased IL-1ß and reactive oxygen species production, and reduced neuronal toxicity, as assessed based on increased neuronal density and upregulation of the NeuN and PSD-95 proteins. Most importantly, oral administration of MCC950 increased neuronal survival, reduced neuroinflammation, extended lifespan, and improved motor dysfunction in R6/2 mice. CONCLUSIONS: Collectively, our findings indicate that MCC950 exerts beneficial effects in a transgenic mouse model of HD and has therapeutic potential for treatment of this devastating neurodegenerative disease.
Subject(s)
Huntington Disease , Neurodegenerative Diseases , Animals , Disease Models, Animal , Huntington Disease/drug therapy , Huntington Disease/genetics , Huntington Disease/metabolism , Inflammasomes/therapeutic use , Male , Mice , Mice, Transgenic , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NeuroprotectionABSTRACT
Polysaccharides from marine organisms produce an important regulatory effect on the mammalian immune system. In this study, the immunomodulatory properties of a polysaccharide that was isolated from the coral Pseudopterogorgia americana (PPA) were investigated. PPA increased the expression levels of tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2), but not inducible nitric oxide synthase and nitric oxide, in macrophages. A mechanistic study revealed that PPA activated macrophages through the toll-like receptor-4 and induced the generation of reactive oxygen species (ROS), increased the phosphorylation levels of protein kinase C (PKC)-α, PKC-δ and mitogen-activated protein kinases (MAPK), and activated NF-κB. The inhibition of ROS and knockdown of PKC-α reduced PPA-mediated TNF-α and IL-6 expression; however, the knockdown of PKC-δ significantly increased PPA-mediated TNF-α expression. In addition, the inhibition of c-Jun N-terminal kinase-1/2 and NF-κB reduced PPA-mediated TNF-α, IL-6 and COX-2 expression. Furthermore, the inhibition of ROS, MAPK and PKC-α/δ reduced PPA-mediated NF-κB activation, indicating that ROS, MAPK and PKC-α/δ function as upstream signals of NF-κB. Finally, PPA treatment decreased the phagocytosis activity of macrophages and reduced cytokine expression in bacteria-infected macrophages. Taken together, our current findings suggest that PPA can potentially play a role in the development of immune modulators in the future.
Subject(s)
Anthozoa/chemistry , Immunologic Factors/pharmacology , Macrophages/immunology , Polysaccharides/pharmacology , Animals , Cyclooxygenase 2/metabolism , Cytokines/biosynthesis , Escherichia coli/drug effects , Escherichia coli/physiology , Humans , Inflammation Mediators/metabolism , Interleukin-6/metabolism , Lipopolysaccharides , Macrophage Activation/drug effects , Macrophages/drug effects , Macrophages/microbiology , Mice , Mitogen-Activated Protein Kinases/metabolism , NF-kappa B/metabolism , Phagocytosis/drug effects , Polysaccharides/chemistry , Protein Kinase C-alpha/metabolism , Protein Kinase C-delta/metabolism , RAW 264.7 Cells , Reactive Oxygen Species/metabolism , THP-1 Cells , Toll-Like Receptor 4/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
BACKGROUND CONTEXT: Intervertebral disc (IVD) degeneration is related to numerous risk factors, including obesity. Leptin, one of the commonly measured adipokines, is proven to play an important role in the pathogenesis of IVD degeneration. In the context of IVD degeneration, matrix metalloproteinase-1 (MMP-1), which is upregulated and activated by leptin, is the most abundant catabolic enzyme. It remains unclear which of the factors mentioned above is most strongly associated with IVD degeneration. PURPOSE: To investigate the influence of MMP-1 in IVD degeneration, we determined the strength of different predictors, including age, sex, magnetic resonance imaging (MRI), Modic changes (MCs), body mass index (BMI), leptin, and MMP-1. This was achieved by assessing the correlation among these factors and histologic degeneration score (HDS). STUDY DESIGN: This study included 89 patients undergoing cervical discectomy for disc herniation, 93 who underwent lumbar discectomy, and 90 control subjects. Herniated disc tissue and plasma were used after the study was approved by the Human Ethics Review Committee at the authors' institution. METHODS: Hematoxylin and eosin (H&E), Alcian blue-PAS and immunohistochemical (IHC) staining were performed to measure the expression levels of leptin and MMP-1. Circulating plasma levels of leptin and MMP-1 were measured using an enzyme-linked immunosorbent assay. To assess the correlation with HDS, measurements of age, sex, BMI, MRI scale, MCs scale, leptin/MMP-1 plasma concentration, and leptin/MMP-1 IHC expression were analyzed. RESULTS: Patients with cervical or lumbar discectomy had significantly higher BMI than controls. Significantly more men than women were involved in the lumbar patients as compared with the cervical patients and the control subjects. After adjustment for age and sex, plasma leptin and leptin IHC score correlated significantly with BMI in patients with cervical or lumbar discectomy. Age, sex, MRI scale, MCs scale, and leptin/MMP-1 plasma concentration were not positively correlated with HDS. HDS was significantly associated with BMI, leptin IHC score, and MMP-1 IHC score. After a stepwise-multiple linear regression analysis to evaluate the strength of the correlations between HDS and various factors, only the MMP-1 IHC score demonstrated an independent association with HDS in patients with degeneration of the cervical or lumbar disc. CONCLUSIONS: MMP-1 IHC score is an independent predictor of the severity of cervical or lumbar IVD degeneration. CLINICAL SIGNIFICANCE: MMP-1 IHC score may be used as an indicator of IVD degeneration.
Subject(s)
Intervertebral Disc Degeneration/blood , Intervertebral Disc Displacement/metabolism , Matrix Metalloproteinase 1/blood , Adult , Biomarkers/blood , Biomarkers/metabolism , Cervical Vertebrae/metabolism , Cervical Vertebrae/pathology , Female , Humans , Intervertebral Disc Degeneration/metabolism , Intervertebral Disc Degeneration/pathology , Intervertebral Disc Displacement/blood , Intervertebral Disc Displacement/pathology , Lumbar Vertebrae/metabolism , Lumbar Vertebrae/pathology , Male , Matrix Metalloproteinase 1/metabolism , Middle AgedABSTRACT
STUDY DESIGN: Retrospective clinical study. OBJECTIVE: To investigate the relationship between the restoration of the lumbar lordosis (LL) and the surgical outcome of patients undergoing spinal fusion for low-grade lumbar degenerative spondylolisthesis. SUMMARY OF BACKGROUND DATA: Correlation between low back pain and the loss of LL in the treatment of low-grade lumbar degenerative spondylolisthesis has seldom been reported. METHODS: Between May 2005 and July 2011, 59 patients with low back pain and neurogenic claudication due to low-grade lumbar degenerative spondylolisthesis underwent spinal decompression and fusion by a senior surgeon. Ten patients were lost to follow-up. The mean age of the remaining 49 patients (10 men and 39 women) was 64.0 years (range, 47-88 y). Patients were categorized on the basis of the spino-pelvic posture: type 1 [pelvic incidence (PI)<45 degrees] (n=12), type 2 (45 degrees≤PI≤60 degrees) (n=24), and type 3 (PI>60 degrees) (n=13). The LL restoration ratio was calculated by the actual LL divided by the predicted LL. The clinical results were evaluated using a visual analogue scale and the Oswestry Disability Index. Postoperative 36-inch spinal films were used to assess the sagittal balance. RESULTS: The mean follow-up period was 43.2 months (range, 28-62 mo). Forty-eight patients showed significant improvement with respect to visual analogue scale and Oswestry Disability Index regardless of whether the LL was restored higher or lower. Postoperative 36-inch spinal films showed the C7 plumb line to be within an average of 4.4 cm (range, 0.6-5.6 cm) from the posterior-superior corner of the S1 vertebrae. CONCLUSIONS: Patients with smaller PI tended to be restored higher, and those patients with a larger PI were more likely to be restored lower. For patients with normal sagittal balance, the surgical outcomes in the treatment of low-grade lumbar degenerative spondylolisthesis with spinal fusion are not correlated with restoration of the LL.
Subject(s)
Lumbar Vertebrae/surgery , Spinal Curvatures/surgery , Spondylolisthesis/surgery , Aged , Aged, 80 and over , Female , Humans , Lumbar Vertebrae/pathology , Male , Middle Aged , Postoperative Complications , Recovery of Function , Retrospective Studies , Severity of Illness Index , Spinal Curvatures/pathology , Spinal Fusion , Spondylolisthesis/pathology , Treatment OutcomeABSTRACT
OBJECTIVES: Although diffusion tensor imaging (DTI) is widely studied to assess the motor outcome after ischaemic stroke, there is paucity of data regarding outcomes of intracerebral haemorrhage (ICH). The aim of this study was to determine the DTI data from different locations along the corticospinal tract (CST) and association to motor outcome. METHODS: We prospectively recruited patients with deep ICH admitted to our hospital from November 2010 to July 2012.Diffusion tensor imaging was performed within 14 âdays after the onset of ICH. Fractional anisotropy (FA) was measured along the CST at corona radiata, perihaematomal oedema, cerebral peduncle and pons. Corticospinal tract integrity was classified into three types by diffusion tensor tractography (DTT): type A with preserved CST, type B with partially interrupted CST and type C with completely interrupted CST. Motor outcome was assessed by Motricity index (MI) at admission, after 1 and 3â months. RESULTS: Forty-eight patients were enrolled with a mean age of 62 âyears. The median time interval from onset of ICH to DTI study was 7â days. The patients in type C had significantly worse MI at admission (P < 0.001), after 1 âmonth (P < 0.001) and after 3 âmonths (P < 0.001) as compared to those with type A and type B. Lower rFA at the corona radiata was significantly correlated with poorer motor outcome at admission, after 1 âmonth and after 3 âmonths. DISCUSSION: Clinical motor outcome of ICH within 2 âweeks can be identified with a statistically significant decrease in rFA at the corona radiata.
Subject(s)
Cerebral Hemorrhage/pathology , Cerebral Hemorrhage/physiopathology , Diffusion Tensor Imaging , Pyramidal Tracts/pathology , Aged , Brain/pathology , Cerebral Hemorrhage/complications , Female , Humans , Male , Middle Aged , Motor Activity , Prospective Studies , Recovery of FunctionABSTRACT
BACKGROUND: Clinical outcomes of intravenous (IV) infusion of zoledronic acid (ZOL) for lumbar interbody fusion surgery (LIFS) remain unknown. We investigated the efficacy of IV ZOL on clinical outcome and bone fusion after LIFS. MATERIALS AND METHODS: We retrospectively analyzed 64 patients with both degenerative lumbar spondylolisthesis and osteoporosis who underwent LIFS from January 2007 to April 2010. All patients were followed up for 2 y. Thirty-two were treated with an IV infusion of ZOL 3 d after surgery and a second injection 1 y later, and the other 32 patients did not receive ZOL. Preoperatively and every 3 mo postoperatively, oswestry disability index questionnaire and visual analog scale (VAS) scores for back and leg were compared. Preoperative and final postoperative follow-up to evaluate for subsequent compression fractures were also performed. Pedicle screw loosening, cage subsidence, and fusion rate were documented 2 y after surgery. RESULTS: At 2-y follow-up, a solid fusion was achieved in 75% of the ZOL group and only 56% of the control group. At final follow up, the incidence of final subsequent vertebral compression fractures (19% of the ZOL group and 51% of the control group, P = 0.006), pedicle screw loosening (18% of the ZOL group and 45% of the control group, P = 0.03), and cage subsidence >2 mm (28% of the ZOL group and only 54% of the control group, P = 0.04) were significantly lower in the ZOL group than in the control group. The ZOL group demonstrated improvement in VAS (for leg pain VAS, 2/10 for the ZOL group and 5/10 for the control group; for back pain VAS, 2/10 for the ZOL group and 6/10 for the control group) and oswestry disability index scores (7/25 for the ZOL group and 16/25 for the control group). CONCLUSIONS: ZOL treatment has beneficial effects on instrumented LIFS both radiographic and clinically. Thus, ZOL treatment can be recommended for osteoporosis patients undergoing LIFS.
Subject(s)
Bone Density Conservation Agents/administration & dosage , Diphosphonates/administration & dosage , Imidazoles/administration & dosage , Osteoporosis/drug therapy , Spinal Fractures/surgery , Spinal Fusion/methods , Aged , Aged, 80 and over , Disability Evaluation , Female , Follow-Up Studies , Fractures, Compression/etiology , Fractures, Compression/surgery , Humans , Infusions, Intravenous , Lumbar Vertebrae/drug effects , Male , Middle Aged , Osteoporosis/complications , Pedicle Screws , Retrospective Studies , Spinal Fractures/etiology , Spinal Fusion/instrumentation , Spondylolisthesis/complications , Spondylolisthesis/drug therapy , Treatment Outcome , Zoledronic AcidABSTRACT
PURPOSE: To report the learning curve of full-endoscopic lumbar discectomy for a surgeon naive to endoscopic surgery but trained in open microdiscectomy. METHODS: From July 2006 to July 2009, 57 patients underwent full-endoscopic lumbar discectomy and 66 underwent open microdiscectomy. The clinical results were evaluated with a visual analog scale (VAS) and the Oswestry Disability Index (ODI). Spearman's coefficient of rank correlation (rho) was used to assess the learning curves for the transforaminal and interlaminar procedures of full-endoscopic lumbar discectomy. RESULTS: After full-endoscopic lumbar discectomy, the VAS and ODI results of the patients followed up were comparable with those of open microdiscectomy. A steep learning curve was observed for the transforaminal procedure, but not the interlaminar procedure. CONCLUSIONS: The learning curve of the transforaminal approach was steep and easy to learn, while the learning curve of the interlaminar approach was flat and hard to master.
Subject(s)
Diskectomy/education , Diskectomy/methods , Endoscopy/education , Endoscopy/methods , Intervertebral Disc Displacement/surgery , Learning Curve , Adult , Disability Evaluation , Education, Medical, Continuing , Female , Follow-Up Studies , Humans , Intervertebral Disc/surgery , Male , Middle Aged , Pain Measurement , Retrospective Studies , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: Retroperitoneoscopic lumbar sympathectomy is a safe and effective treatment for plantar hyperhidrosis. OBJECTIVE: To evaluate the safety and feasibility of laparoendoscopic single-site retroperitoneal lumbar sympathectomy in plantar hyperhidrosis. METHODS: Bilateral laparoendoscopic single-site retroperitoneal lumbar sympathectomy was performed in a 27-year-old man who suffered from excessive sweating from the soles of the feet. A homemade single port was created with an Alexis wound retractor through a 2.5-cm incision at the tip of the 12th rib. With conventional 5-mm laparoscopy and instruments, retroperitoneal lumbar sympathectomy was performed. RESULTS: The procedure was completed successfully without any complications and with minimal blood loss. The operative time was 110 and 80 minutes for the procedure on the left and right sides. The perioperative course and postoperative course were uneventful. The patient had anhidrosis of both feet after surgery with Hyperhidrosis Disease Severity Scale score of 1 at the 1-month follow-up. CONCLUSION: Laparoendoscopic single-site retroperitoneal lumbar sympathectomy is a safe and feasible procedure according to our initial experience.