The Relationship Between MRI Findings of Posterior Ligamentous Complex and Lumbar Instability in Degenerative Spondylolisthesis.

Background: To determine the factors in posterior ligamentous complex indicating lumbar instability in patients diagnosed with degenerative spondylolisthesis on conventional magnetic resonance imaging (MRI). Methods: We retrospectively analyzed patients who underwent PLIF surgery for degenerative spondylolisthesis at our institution between 2018 and 2020 and who had complete eligible preoperative imaging data for review and study, including lumbar MRI and anteroposterior and flexion-extension radiographs. Results: Fifty-three patients were confirmed to have lumbar instability (Unstable Group, 44%), while sixty-seven patients (Stable Group, 56%) did not have instability on radiographs. The patients in the stable group had more advanced status of the degeneration of intervertebral disc than in the unstable group (p<0.05). The degeneration of supraspinous ligament (SSL) was more severe in the unstable group (p<0.05). Compared with the patients with rotatory instability, advanced degeneration of interspinous ligament (ISL) and SSL was observed in patients with translatory instability (p<0.05). However, there was no significant difference with regard to the height of the spinous process and the interspinous distance in patients with or without instability. Conclusion: This MRI analysis showed that abnormal segmental motion is closely associated with the pathological characteristics of supraspinal ligament. Advanced degeneration of SSL in patients with degenerative spondylolisthesis should raise the suspicion for lumbar instability and additional evaluations. The status of ISL and ligamentum flavum (LF) may not be helpful for the diagnosis of lumbar instability. Functional radiographs combined with MRI may provide valuable information when diagnosing lumbar instability in patients with mechanical back pain.

Nimbolide targeting SIRT1 mitigates intervertebral disc degeneration by reprogramming cholesterol metabolism and inhibiting inflammatory signaling.

Inflammation, abnormal cholesterol metabolism, and macrophage infiltration are involved in the destruction of the extracellular matrix of the nucleus pulposus (NP), culminating in intervertebral disc degeneration (IDD). Whether nimbolide (Nim), a natural extract, can alleviate IDD is unclear. In this study, we demonstrated that Nim promotes cholesterol efflux and inhibits the activation of the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways by activating sirtuin 1 (SIRT1) in nucleus pulposus cells (NPCs) during inflammation. Thus, Nim balanced matrix anabolism and catabolism of NPCs. However, the inhibition of SIRT1 significantly attenuated the effects of Nim. We also found that Nim promoted the expression of SIRT1 in RAW 264.7, which enhanced the proportion of M2 macrophages by facilitating cholesterol homeostasis reprogramming and impeded M1-like macrophages polarization by blocking the activation of inflammatory signaling. Based on these results, Nim can improve the microenvironment and facilitate matrix metabolism equilibrium in NPCs. Furthermore, in vivo treatment with Nim delayed IDD progression by boosting SIRT1 expression, modulating macrophage polarization and preserving the extracellular matrix. In conclusion, Nim may represent a novel therapeutic strategy for treating IDD.

A Comparison of Percutaneous Kyphoplasty with High-Viscosity and Low-Viscosity Bone Cement for Treatment of Osteoporotic Vertebral Compression Fractures: A Retrospective Study.

Background: Osteoporotic vertebral compression fracture (OVCF) has become a health issue of worldwide concern. Percutaneous kyphoplasty (PKP) is one of the main surgical methods for OVCFs. This study aimed to evaluate and compare the clinical efficacy and safety of PKP with high- and low-viscosity bone cement for OVCFs. Methods: Totally 62 patients with single-level OVCF were enrolled in this study from December 2018 to April 2021. Among them, 32 cases underwent PKP with high-viscosity bone cement, while 30 cases underwent PKP with low-viscosity bone cement. Visual analog scale (VAS) scores and Oswestry disability index (ODI) scores were used in the pre- and post-operative period to assess patients' rehabilitation. Compression rates of anterior vertebra height (AVH) and posterior vertebra height (PVH) were analyzed to evaluate the restoration of vertebra height. Leakage rates and locations were recorded to show clinical safety. Results: VAS and ODI scores both significantly improved in 2 groups at 1 day, 1 month, and 3 months after surgery. Compression rates of AVH and PVH at 1 day and 3 months after PKP were lower than those before surgery. However, there was no significant difference in VAS scores, ODI scores, and compression rates between both groups. However, PKP with high-viscosity bone cement achieved a lower bone cement leakage rate significantly, which showed the safety of high-viscosity bone cement in PKP. Conclusions: PKP with high- and low-viscosity bone cement both improved the recovery of patients and restored vertebra heights. Notably, PKP with high-viscosity bone cement can achieve favorable clinical outcomes as well as lower bone cement leakage rate.

Comparison of 3-level anterior cervical discectomy and fusion and open-door laminoplasty in cervical sagittal balance: A retrospective study.

Objective: To compare the clinical efficacy and radiological outcomes of 3-level anterior cervical discectomy and fusion (ACDF) and open-door laminoplasty (LP). Methods: A total of 74 patients from January 2017 to January 2020 were enrolled in this retrospective study. There were two groups. Group A (30 cases) received 3-level ACDF, while Group B (44 cases) received open-door LP. Clinical evaluation included perioperative parameters, Neck Disability Index (NDI), and Japanese Orthopaedic Association (JOA) scores. Radiological evaluation included cervical curve depth (CCD), C2-7 angle, C2-7 sagittal vertical axis (cSVA), C7 slope (C7S), and T1 slope (T1S). Results: Perioperative parameters such as blood loss, drainage volume after surgery, and hospital stay of patients in Group A were significantly less than those in Group B (P < .001). NDI scores decreased and JOA scores increased significantly after surgery in both groups (P < .05). There was a significant difference in both scores postoperatively and at 1 month after surgery between the two groups (P < .05). CCD and C2-7 angle of Group A increased significantly postoperatively at 1 month after surgery and at final follow-up (FFU) (P < .05). There was a significant difference in CCD and the C2-7 angle between the two groups postoperatively at 1 month after surgery and at FFU (P < .05). T1S increased significantly in Group A postoperatively and at 1 month after surgery (P < .05). Conclusion: 3-level ACDF and open-door LP achieved favorable clinical outcomes and ACDF benefited patients in the early stage of rehabilitation. Compared with open-door LP, 3-level ACDF had advantages of reconstructing cervical lordosis with increased CCD and C2-7 angle.

Percutaneous kyphoplasty for the treatment of diffuse idiopathic skeletal hyperostosis with vertebral fractures: A case report and treatment review.

Diffuse idiopathic skeletal hyperostosis (DISH) is a systemic metabolic condition characterized by new bone formation mainly at the anterolateral spine. Surgery such as screw fixation is commonly used for DISH patients who also suffer from vertebral fractures. In this case report, we share a DISH case with lumbar vertebral fracture and osteoporosis who underwent percutaneous kyphoplasty plus braces and medication. Percutaneous kyphoplasty, considered as minimally invasive surgery, may be another treatment option with the advantages of less trauma and faster recovery. The clinical information and radiological findings are described and treatments for DISH with vertebral fractures are then briefly reviewed.

Renal UTX-PHGDH-serine axis regulates metabolic disorders in the kidney and liver.

Global obesity epidemics impacts human health and causes obesity-related illnesses, including the obesity-related kidney and liver diseases. UTX, a histone H3K27 demethylase, plays important roles in development and differentiation. Here we show that kidney-specific knockout Utx inhibits high-fat diet induced lipid accumulation in the kidney and liver via upregulating circulating serine levels. Mechanistically, UTX recruits E3 ligase RNF114 to ubiquitinate phosphoglycerate dehydrogenase, the rate limiting enzyme for de novo serine synthesis, at Lys310 and Lys330, which leads to its degradation, and thus suppresses renal and circulating serine levels. Consistently, phosphoglycerate dehydrogenase and serine levels are markedly downregulated in human subjects with diabetic kidney disease or obesity-related renal dysfunction. Notably, oral administration of serine ameliorates high-fat diet induced fatty liver and renal dysfunction, suggesting a potential approach against obesity related metabolic disorders. Together, our results reveal a metabolic homeostasis regulation mediated by a renal UTX-PHGDH-serine axis.

Influence of Different Surgical Timing after Percutaneous Kyphoplasty for Osteoporotic Vertebral Compression Fractures: A Retrospective Study.

Background: A large number of people suffer from osteoporotic vertebral compression fractures (OVCFs) worldwide. Percutaneous kyphoplasty (PKP), considered a minimally invasive surgery, has been widely used to treat OVCFs and achieves satisfactory outcomes. However, the surgical timing of PKP is still under discussion. Methods: A total of 149 patients were enrolled in the study and were divided into 3 groups according to different surgical timing. Group A (n = 52) included patients who required emergency surgery. Group B (n = 50) included patients who required surgery around a week after injury. Group C (n = 47) included patients who required surgery a month or more after injury. Characteristics of patients and radiological images were recorded. The Visual Analog Scale (VAS) scores and the Oswestry Disability Index (ODI) scores were analyzed before, 1 day, 1 month, and 6 months after surgery. In addition, compression rates of anterior vertebral height (AVH) were calculated and the kyphosis Cobb angle was measured before and after surgery. Results: There was a significant difference in the VAS and ODI scores between the three groups at 1 day, 1 month, and 6 months after PKP. The VAS and ODI scores of Group C were higher than those of Groups A and B. The AVH compression rates of Group C were significantly higher than those of Groups A and B postoperatively 1 day, 1 month, and 6 months. The kyphosis Cobb angles in Group C was significantly larger than those in Groups A and B at 1 day and 1 month after PKP. Conclusions: Emergency PKP showed more advantages in both clinical and radiological outcomes. We recommend early PKP for the treatment of OVCFs.

Mecp2 protects kidney from ischemia-reperfusion injury through transcriptional repressing IL-6/STAT3 signaling.

Rationale: Ischemia-reperfusion (IR) induced acute kidney injury (AKI) causes serious clinical problems associated with high morbidity and mortality. Mecp2 is a methyl-CpG binding protein, its mutation or deletion causes a neurodevelopment disease called Rett syndrome. Notably, some Rett syndrome patients present urological dysfunctions. It remains unclear whether and how Mecp2 affects AKI. Methods: Renal tubular cell specific Mecp2 deletion mice challenged with IR injury were used to investigate the effects of Mecp2 on renal tubular damage, function, cell death, fibrosis and inflammation. Cultured renal epithelial cell lines were transfected with wildtype or different domain-deletion mutants of Mecp2 to study the effects of Mecp2 on Il-6/STAT3 signaling. Results: Our results indicated rapidly upregulated Mecp2 upon acute in vivo and in vitro renal injury. Notably, increased tubular MeCP2 staining was also found in the renal sections of AKI patients. Furthermore, ablation of Mecp2 aggravated renal injury, and promoted renal cell death, inflammation, and fibrosis. Mechanistically, through its transcriptional repression domain, Mecp2 bound to the promoter of proinflammatory cytokine Il-6 to negatively regulate its expression, thus inhibiting STAT3 activation. Conclusions: A novel protective role of Mecp2 against AKI via repressing the Il-6/STAT3 axis was suggested.

Histone demethylase UTX aggravates acetaminophen overdose induced hepatotoxicity through dual mechanisms.

Acetaminophen (APAP) overdose is a major cause of acute liver failure, while the underlying mechanisms of APAP hepatotoxicity are not fully understood. Recently, emerging evidence suggests that epigenetic enzymes play roles in APAP-induced liver injury. Here, we found that Utx (ubiquitously transcribed tetratricopeptide repeat, X chromosome, also known as KDM6A), a X-linked histone demethylase which removes the di- and tri-methyl groups from histone H3K27, was markedly induced in the liver of APAP-overdosed female mice. Hepatic deletion of Utx suppressed APAP overdose-induced hepatotoxicity in female but not male mice. RNA-sequencing analysis suggested that Utx deficiency in female mice upregulated antitoxic phase II conjugating enzymes, including sulfotransferase family 2 A member 1 (Sult2a1), thus reduces the amount of toxic APAP metabolites in injured liver; while Utx deficiency also alleviated ER stress through downregulating transcription of ER stress genes including Atf4, Atf3, and Chop. Mechanistically, Utx promoted transcription of ER stress related genes in a demethylase activity-dependent manner, while repressed Sult2a1 expression through mediating H3K27ac levels independent of its demethylase activity. Moreover, overexpression of Sult2a1 in the liver of female mice rescued APAP-overdose induced liver injury. Together, our results indicated a novel UTX-Sult2a1 axis for the prevention or treatment of APAP-induced liver injury.

Emerging physiological and pathological roles of MeCP2 in non-neurological systems.

Numerous neurological and non-neurological disorders are associated with dysfunction of epigenetic modulators, and methyl CpG binding protein 2 (MeCP2) is one of such proteins. Initially identified as a transcriptional repressor, MeCP2 specifically binds to methylated DNA, and mutations of MeCP2 have been shown to cause Rett syndrome (RTT), a severe neurological disorder. Recently, accumulating evidence suggests that ubiquitously expressed MeCP2 also plays a central role in non-neurological disorders including cardiac dysfunction, liver injury, respiratory disorders, urological dysfunction, adipose tissue metabolism disorders, movement abnormality and inflammatory responses in a DNA methylation dependent or independent manner. Despite significant progresses in our understanding of MeCP2 over the last few decades, there is still a considerable knowledge gap to translate the in vitro and in vivo experimental findings into therapeutic interventions. In this review, we provide a synopsis of the role of MeCP2 in the pathophysiology of non-neurological disorders, MeCP2-based research directions and therapeutic strategies for non-neurological disorders are also discussed.

Loss of histone lysine methyltransferase EZH2 confers resistance to tyrosine kinase inhibitors in non-small cell lung cancer.

Tyrosine kinase inhibitor (TKI) treatment is the first-line therapy for non-small cell lung cancer (NSCLC) caused by activating mutations of epidermal growth factor receptor (EGFR). However, acquired resistance to EGFR-TKI occurs almost inevitably. Aberrant activation of proto-oncogene MET has been known to confer EGFR-TKI resistance; however, the mechanisms involved remains unclear. Recent evidence implicates epigenetic heterogeneity as playing roles in cancer drug resistance, whereas links involving epigenetic heterogeneity and MET in NSCLC remain poorly understood. We found that expression of EZH2, a histone methyltransferase, was negatively correlated with MET activation and EGFR-TKI resistance in NSCLC cells and clinical samples, suggesting the potential for EZH2 to be used as a biomarker for EGFR-TKI sensitivity. Knockdown or inhibition of EZH2 up-regulated MET expression and phosphorylation, and elevated proliferation and EGFR-TKI resistance of cells in vitro. Meanwhile, inhibition of MET or PI3K/AKT enhanced EZH2 levels and restored sensitivity to EGFR-TKI. These findings indicate a "MET-AKT-EZH2" feedback loop regulating EGFR-TKI-resistance. Furthermore, combination therapy of PI3K/AKT inhibition and EGFR-TKI, which interrupts the loop, enhanced tumor-suppressive effects in an EGFR-TKI-resistant xenograft model, indicating a potential approach against drug resistance in NSCLC.

Histone demethylase UTX is a therapeutic target for diabetic kidney disease.

KEY POINTS: Diabetic kidney disease (DKD) is a major complication of diabetes. We found that UTX (ubiquitously transcribed tetratricopeptide repeat on chromosome X, also known as KDM6A), a histone demethylase, was upregulated in the renal mesangial and tubular cells of diabetic mice and DKD patients. In cultured renal mesangial and tubular cells, UTX overexpression promoted palmitic acid-induced elevation of inflammation and DNA damage, whereas UTX knockdown or GSK-J4 treatment showed the opposite effects. We found that UTX demethylase activity-dependently regulated the transcription of inflammatory genes and apoptosis; moreover, UTX bound with p53 and p53-dependently exacerbated DNA damage. Administration of GSK-J4, an H3K27 demethylase inhibitor, ameliorated the diabetes-induced renal abnormalities in db/db mice, an animal model of type 2 diabetes. These results revealed the possible mechanisms underlying the regulation of histone methylation in DKD and suggest UTX as a potential therapeutic target for DKD. ABSTRACT: Diabetic kidney disease (DKD) is a microvascular complication of diabetes and the leading cause of end-stage kidney disease worldwide without effective therapy available. UTX (ubiquitously transcribed tetratricopeptide repeat on chromosome X, also known as KDM6A), a histone demethylase that removes the di- and tri-methyl groups from histone H3K27, plays important biological roles in gene activation, cell fate control and life span regulation in Caenorhabditis elegans. In the present study, we report upregulated UTX in the kidneys of diabetic mice and DKD patients. Administration of GSK-J4, an H3K27 demethylase inhibitor, ameliorated the diabetes-induced renal dysfunction, abnormal morphology, inflammation, apoptosis and DNA damage in db/db mice, comprising an animal model of type 2 diabetes. In cultured renal mesanglial and tubular cells, UTX overexpression promoted palmitic acid induced elevation of inflammation and DNA damage, whereas UTX knockdown or GSK-J4 treatment showed the opposite effects. Mechanistically, we found that UTX demethylase activity-dependently regulated the transcription of inflammatory genes; moreover, UTX bound with p53 and p53-dependently exacerbated DNA damage. Collectively, our results suggest UTX as a potential therapeutic target for DKD.

[Dictamni Cortex powder-induced liver injury based on integrated evidence chain].

A typical clinical case of taking Dictamni Cortex(Baixianpi) powder was analyzed to study liver damage caused by Dictamni Cortex. Liver damage was diagnosed according to the integrated evidence chain method recommended by the Guideline for Diagnosis and Treatment of Herb-Induced Liver Injury. By analyzing clinical history and biochemistry and imaging examinations, underlying diseases, such as viral hepatitis, autoimmune liver disease and alcoholic liver disease, were excluded. Through the investigation of medication history, we made it clear that the patient only took Dictamni Cortex powder during the period, and thus suspected that the liver injury was induced by Dictamni Cortex. Furthermore, the quality of the drug was tested, and the results showed it was consistent with the quality standard of Chinese Pharmacopoeia. DNA barcoding showed that the drug was 100% similar with Dictamnus dasycarpus. Moreover, exogenous harmful substances and chemical drug additions were tested, and the results showed that the content of heavy metal, pesticide residues and microbial toxin were consistent with the required standards, and no chemical drug additions were found in Agilent Fake TCM-Drugs database. In summary, we confirmed that the clinical case of drug-induced liver injury was induced by D. dasycarpus with the dose of 15 g•d⁻¹, which exceeded the prescribed amount of Chinese Pharmacopoeia. According to the Guideline for Diagnosis and Treatment of Herb-Induced Liver Injury, the case of drug-induced liver injury induced by D. dasycarpus was confirmed, which provided a direct and reliable evidence for the study of risk of liver injury induced by D. dasycarpus and its relevant preparations.

Efficacy of Compound Kushen Injection in Relieving Cancer-Related Pain: A Systematic Review and Meta-Analysis.

Despite widespread popular use of complementary and alternative medicine (CAM) therapies, a rigorous evidence based on the efficacy of compound kushen injection (CKI) for cancer-related pain is lacking. In this study, we evaluated the efficacy and safety of compound kushen injection and provided information for current or future research and clinical application. Sixteen trials were identified with a total of 1564 patients. The total pain relief rate of CKI plus chemotherapy is better than chemotherapy except for colorectal cancer. The treatment groups achieved a reduction in the incidences of leukopenia and gastrointestinal, hepatic, and renal functional lesion. However, there is paucity of multi-institutional RCTs evaluating compound kushen injection for cancer pain with adequate power, duration, and sham control. The quantity and quality of RCTs are lower so that we still have to boost the research level through scientific design and normative report.