Rapid and nondestructive identification of adulterate capsules by NIR spectroscopy combined with chemometrics.

This study aims to develop a rapid and non-destructive method to identify counterfeit and substandard drugs, addressing the critical need for better quality control in drug production. According to the reasons for counterfeit products in actual production, the commonly used solid preparation excipients such as HPMC, MCC, Mg-St and Pregelatinized Starch, as well as three chemical drugs with similar efficacy to Guizhi-Fuling (GZFL) Capsule as adulterants, including Aspirin, Ibuprofen and Sinomenine Hydrochloride were selected and designed as adulteration samples with different levels of adulteration. NIR spectra were collected in a non-invasive mode and analyzed by one-class classification methods. The feasibility of using Near-infrared (NIR) spectroscopy as a detection method to qualitatively identify adulterated samples was explored at three packaging levels of powder, intact capsules and capsules in PVC. The differences between the samples were analyzed by NIR spectra comparison, cluster analysis and principal component analysis. The performance of SVM, OCPLS and DD-SIMCA models in dealing with the authentication of genuine and counterfeit products was established and compared. The results show that the spectra contain sample information and the adulterated samples could be discriminated correctly by established models. Moreover, applying appropriate spectral preprocessing methods can further improve the model's performance. In addition, a PLS regression model was developed to predict the adulteration levels of the three packing level samples, which yielded satisfactory results. This study highlights the potential of NIR spectroscopy combined with Chemometrics as a rapid and non-destructive testing analysis method to accurately identify counterfeit and substandard drugs, thereby ensuring drug quality.

The deubiquitinase UCHL1 negatively controls osteoclastogenesis by regulating TAZ/NFATC1 signalling.

The ubiquitin‒proteasome system (UPS) plays a key role in maintaining protein homeostasis and bone remodelling. However, the role of deubiquitinating enzymes (DUBs) in bone resorption is still not well defined. Here, we identified the deubiquitinase ubiquitin C-terminal hydrolase 1 (UCHL1) as a negative regulator of osteoclastogenesis by using the GEO database, proteomic analysis, and RNAi. Osteoclast-specific UCHL1 conditional knockout mice exhibited a severe osteoporosis phenotype in an ovariectomized model. Mechanistically, UCHL1 deubiquitinated and stabilized the transcriptional coactivator with PDZ-binding motif (TAZ) at the K46 residue, thereby inhibiting osteoclastogenesis. The TAZ protein underwent K48-linked polyubiquitination, which was degraded by UCHL1. As a substrate of UCHL1, TAZ regulates NFATC1 through a nontranscriptional coactivator function by competing with calcineurin A (CNA) for binding to NFATC1, which inhibits NFATC1 dephosphorylation and nuclear transport to impede osteoclastogenesis. Moreover, overexpression of UCHL1 locally alleviated acute and chronic bone loss. These findings suggest that activating UCHL1 may serve as a novel therapeutic approach targeting bone loss in various bone pathological states.

[Dissolution test and evaluation of Guizhi Fuling Capsules].

Because of the complex components, simple content determination can hardly reflect the overall quality of Guizhi Fuling Capsules. Therefore, it is necessary to carry out a multi-component dissolution test. The variability of quality among different batches of products from different manufacturers is a common problem of Chinese medicine solid preparations. To comprehensively control the quality of Guizhi Fuling Capsules, we studied the dissolution behaviors of 7 index components in the capsules under different conditions, and investigated the consistency of dissolution behaviors among different batches of products from the same manufacturer. The basket method of general rule 0931 in Chinese Pharmacopoeia was adopted, and the rotating speeds were set at 50, 75, and 100 r·min~(-1), respectively. The hydrochloric acid solution(pH 1.2), acetate buffer solution(pH 4.0), pure water, and phosphate buffer solution(pH 6.8) were used as the dissolution media. Automatic sampling was carried out at the time points of 5, 10, 20, 30, 45, and 60 min, respectively. The cumulative dissolution of 7 index components was measured through ultra-performance liquid chromatography(UPLC). The difference factor f_1 and similarity factor f_2 were calculated to comprehensively evaluate the similarity of the dissolution curves among 8 batches of Guizhi Fuling Capsules, and a variety of dissolution and release equations were fitted. The results showed that multiple components had faster dissolution rates at higher rotating speed and in hydrochloric acid medium. The 8 batches of Guizhi Fuling capsules showed the average f_1 value lower than 15 and the average f_2 value higher than 50, which indicated that different batches of products had similar dissolution behaviors. Most components had synchronous dissolution behaviors and similar release cha-racteristics. This study provides a reference for the quality consistency evaluation among batches, processing optimization, and dosage form improvement of Guizhi Fuling Capsules.

Methyl 3,4-dihydroxybenzoate inhibits RANKL-induced osteoclastogenesis via Nrf2 signaling in vitro and suppresses LPS-induced osteolysis and ovariectomy-induced osteoporosis in vivo.

Osteoporosis deteriorates bone mass and biomechanical strength and is life-threatening to the elderly. In this study, we show that methyl 3,4-dihydroxybenzoate (MDHB), an antioxidant small-molecule compound extracted from natural plants, inhibits receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclastogenesis in vitro. Furthermore, MDHB attenuates the activation of mitogen-activated protein kinase (MAPK) and NF-κB pathways by reducing the levels of reactive oxygen species (ROS), which leads to downregulated protein expression of c-Fos and nuclear factor of activated T cells c1 (NFATc1). We also confirm that MDHB upregulates the protein expression of nuclear factor-erythroid 2-related factor 2 (Nrf2), an important transcription factor involved in ROS regulation, by inhibiting the ubiquitination-mediated proteasomal degradation of Nrf2. Next, animal experiments show that MDHB has an effective therapeutic effect on lipopolysaccharide (LPS)- and ovariectomized (OVX)-induced bone loss in mice. Our study demonstrates that MDHB can upregulate Nrf2 and suppress excessive osteoclast activity in mice to treat osteoporosis.

[Short-segment pedicle screw fixation combined with vertebroplasty for the treatment of Kümmell disease with kyphosis].

OBJECTIVE: To explore the clinical effects of posterior short-segment pedicle screw internal fixation combined with vertebroplasty for the treatment of Kümmell disease with kyphosis. METHODS: Twenty-four patients with Kümmell disease complicated with kyphosis treated by posterior short-segment pedicle screw internal fixation combined with vertebroplasty from January 2016 to December 2018 were retrospectively analyzed, including 6 males and 18 females, aged 63 to 85 (73.1±6.5) years old. The clinical effect was evaluate by visual analogue scale (VAS), Oswestry Disability Index (ODI), the anterior height of injured vertebral body, and the sagittal Cobb angle of the affected segment beforeoperation, at 3 days and final follow up after operation. And the surgical complications were observed. RESULTS: All 24 patients were followed up from 12 to 24 months with an average of (15.5±3.2) months. The VAS score was decreased from 5.21±1.06 preoperatively to 2.38±0.58 at 3 days postoperatively and 1.71±0.75 at final follow-up;ODI was decreased from (50.4±13.5)% preoperatively to (20.9±8.0)% at 3 days postoperatively and (16.7±9.6)% at final follow-up;the anterior height of injured vertebral body was restored from (8.0±4.2) mm before surgery to (18.1±5.0) mm at 3 days after surgery and (16.8±5.1) mm at final follow up;the sagittal Cobb angle of affected segment was decreased from (19.5±6.3)° preoperatively to (7.6±2.1)° at 3 days after surgery and(8.4±1.7)° at final follow-up. VAS, ODI, anterior height of injured vertebral body, and sagittal Cobb angle of affected segment were significantly improved at 3 days after operation and at final follow-up (P<0.05). Two patients had complications, including asymptomaticcement leakage in 1 patient and superficial wound infection in 1 patient. CONCLUSION: Posterior short-segment pedicle screw internal fixation combined with vertebroplasty for the treatment of Kümmell disease with kyphosis has relatively small surgical trauma, excellent clinical results, good vertebral height recovery, satisfactory correction of kyphotic angle, and fewer complications, etc. It is a safe and effective surgical method to treat Kümmell disease with kyphosis.

Homocysteine induces oxidative stress and ferroptosis of nucleus pulposus via enhancing methylation of GPX4.

Homocysteine (Hcy) is an amino acid involved in gene methylation. Plasma concentration of Hcy is elevated in the pathological condition hyperhomocysteinemia (HHcy), which increases the risk of disorders of the vascular, nervous and musculoskeletal systems, including chondrocyte dysfunction. The present study aimed to explore the role of Hcy in intervertebral disc degeneration (IVDD), using a range of techniques. A clinical epidemiological study showed that HHcy is an independent risk factor for human IVDD. Cell culture using rat nucleus pulposus cells showed that Hcy promotes a degenerative cell phenotype (involving increased oxidative stress and cell death by ferroptosis) which is mediated by upregulated methylation of GPX4. An in-vivo mouse 'puncture' model of IVDD showed that folic acid (which is used to treat HHcy in humans) reduced the ability of diet-induced HHcy to promote IVDD. We conclude that Hcy upregulates oxidative stress and ferroptosis in the nucleus pulposus via enhancing GPX4 methylation, and is a new contributing factor in IVDD.

The Effects of Acupuncture on Chronic Knee Pain Due to Osteoarthritis: A Meta-Analysis.

BACKGROUND: Acupuncture reportedly relieves chronic knee pain and improves physical function in patients diagnosed with osteoarthritis, but the duration of these effects is controversial. The aim of this study was to evaluate the temporal effects of acupuncture on chronic knee pain due to knee osteoarthritis by means of a meta-analysis. METHODS: The PubMed, Embase, and Cochrane Central Register of Controlled Trials databases were searched for studies published through March 2015. Ten randomized controlled trials of acupuncture compared with sham acupuncture, usual care, or no intervention for chronic knee pain in patients with clinically diagnosed or radiographically confirmed knee osteoarthritis were included. All of the studies were available in English. Weighted mean differences (WMDs), 95% confidence intervals (CIs), publication bias, and heterogeneity were calculated. RESULTS: The acupuncture groups showed superior pain improvement (p < 0.001; WMD = -1.24 [95% CI, -1.92 to -0.56]; I(2) > 50%) and physical function (p < 0.001; WMD = 4.61 [95% CI, 2.24 to 6.97]; I(2) > 50%) in the short term (up to 13 weeks). The acupuncture groups showed superior physical function (p = 0.016; WMD = 2.73 [95% CI, 0.51 to 4.94]; I(2) > 50%) but not superior pain improvement (p = 0.199; WMD = -0.55 [95% CI, -1.39 to 0.29]; I(2) > 50%) in the long term (up to 26 weeks). Subgroup analysis revealed that the acupuncture groups tended to have better outcomes compared with the controls. Significant publication bias was not detected (p > 0.05), but the heterogeneity of the studies was substantial. CONCLUSIONS: This meta-analysis demonstrates that acupuncture can improve short and long-term physical function, but it appears to provide only short-term pain relief in patients with chronic knee pain due to osteoarthritis. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

New Levels of Vertebral Compression Fractures after Percutaneous Kyphoplasty: Retrospective Analysis of Styles and Risk Factors.

BACKGROUND: The causes of subsequent vertebral fractures after kyphoplasty are debated. It is reported that most new vertebral fractures after kyphoplasty develop in adjacent vertebrae. OBJECTIVES: We explored whether kyphoplasty increases the incidence of adjacent vertebral fractures and identified risk factors for new vertebral compression fractures (VCFs) after kyphoplasty. STUDY DESIGN: Retrospective study. SETTING: Inpatient population of a single center. METHODS: We studied 356 patients treated with kyphoplasty from January 2008 to March 2012. Among those patients, there were 35 new VCFs after kyphoplasty. Subsequently, these patients were divided into 2 groups: an "adjacent fracture" group and a "nonadjacent fracture" group. In addition, all patients treated with kyphoplasty were further assigned to either a "new fracture" group or a "no fracture" group. RESULTS: The occurrence of new VCFs in the "nonadjacent fracture" group was significantly higher than that in the "adjacent fracture" group. The average bone mineral density (BMD) of the spine was -3.95 in the "new fracture" group and -2.86 in the "no fracture" group. The risk of new vertebral fracture increased as the bone mineral density decreased (P < 0.05). The morbidity of women was significantly higher in the "new fracture" group (94.29%) than in the "no fracture" group (77.88%) (P = 0.025). LIMITATIONS: Retrospective study at a single center. CONCLUSION: New VCFs after kyphoplasty occurred most often in nonadjacent vertebrae. VCFs after kyphoplasty were common in patients with low bone mineral density and in women, suggesting that osteoporosis is an underlying mechanism. INSTITUTIONAL REVIEW: This study was approved by the institutional review board.

Re-fractures of non fracture vertebral body after percutaneous kyphoplasty / 中华骨科杂志

Objective To investigate the causes of re-fractures of non fracture vertebral body after percutaneous kyphoplasty (PKP).Methods 512 patients (618 vertebral bodies) treated with PKP because of osteoporosis VCFs were recruited from June 2010 to June 2014.There were 107 males (121 vertebral bodies) and 405 females (497 vertebral bodies) with the mean age of 70.38±7.59 years old (51 to 91 years).There were 406 single segment fracture and 106 double segment fractures cases,and the fracture segments were T4 to L5.The T value of the patients' bone mineral density (BMD) was from-1.0 to-5.2 SD.The clinic characteristics of all the patients including age,sex,body weight,body height,body mass index (BMI),BMD score of the spine,volume of bone cement,restoration rate of anterior/middle vertebral height,postoperative complications (pulmonary embolism,bone cement leakage,nerve injury),and treated vertebral level were analyzed.Results 52 patients (10.16％,52/512) experienced refractures of non fracture vertebral body after kyphoplasty,and 4 experienced re-fracture of the fracture vertebral body after kyphoplasty.The average age of the 52 patients was 71.88±7.74 years old,meanwhile,the ratio of female was 94.23％ (49/52),the mean T value of BMD-4.03±0.60 SD,the ratio of initial double segment fractures 51.92％ (27/52).In addition,among the 456 cases with no fracture,the average age was 70.21±7.56 years,the ratio of female was 77.19％ (352/456);the mean T value of BMD was-2.89±0.55 SD;the ratio of initial double segment fractures was 17.32％(79/456).The data above (age,T value of BMD and initial double segment fractures) were all with statistical significant differences.Whereas the BMI,volume of bone cement,intervertebral disc leakage and restoration rate of anterior/middle vertebral height had no significant difference between the two groups.Furthermore,in the re-fracture of non fracture vertebral body group,32 cases (61.54％,32/52) were nonadjacent fractures,and 20 (38.46％,20/52) were adjacent fractures.Conclusion Osteoporosis degree,female and initial double segment fractures were major risk factors in the development of re-fracture of non fracture vertebral body after PKP.

Is unilateral kyphoplasty as effective and safe as bilateral kyphoplasties for osteoporotic vertebral compression fractures? A meta-analysis.

BACKGROUND: An osteoporotic vertebral compression fracture is a common condition in elderly people, especially women. The percutaneous kyphoplasty is an effective treatment for osteoporotic vertebral compression fractures. Controversy remains regarding whether a unilateral or a bilateral approach is superior, and to our knowledge, there have been no large studies comparing these two approaches, therefore a meta-analysis synthesizing the data on this question is warranted. QUESTIONS/PURPOSES: We asked the following questions: (1) Is there evidence to suggest a benefit in clinical outcome as assessed by the VAS and Oswestry Disability Index of a unilateral kyphoplasty or bilateral kyphoplasties? (2) Are the complications associated with the two approaches different? (3) Do the procedures result in different kyphosis angle reduction or anterior vertebral height restoration? (4) Is the surgical time for the procedures different? METHODS: We searched the Cochrane Library, PubMed MEDLINE, EMBASE, Web of Knowledge MEDLINE (January 1980 to June 2013), and reference lists of eligible prospective studies. The levels of the evidence and recommendations were assessed using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system. Five studies encompassing 253 patients met the inclusion criteria. RESULTS: The short- and long-term clinical outcomes as assessed by the VAS and Oswestry Disability Index showed no differences between unilateral and bilateral kyphoplasties (p = 0.41, p = 0.60 for VAS; p = 0.10, p = 0.36 for Oswestry Disability Index). There were no differences in complications such as cement leakage and adjacent vertebral fractures associated with the two approaches (p = 0.43 and p = 0.95). The kyphosis angle reduction and anterior vertebral height restoration showed no difference between the two approaches (p = 0.34 and p = 0.46). The unilateral approach was shorter in terms of surgical time (mean difference, -24.98; p < 0.0001). The overall GRADE system evidence quality was very low, with only high evidence for operation time, which lessens our confidence in recommendations. CONCLUSIONS: Unilateral and bilateral percutaneous kyphoplasties appear to be safe and effective for treating osteoporotic vertebral compression fractures. No clinically important differences were found between them. Considering less operation time and less cost, we suggest that a unilateral percutaneous kyphoplasty is advantageous, but because of the poor quality of the evidence, high-quality randomized controlled trials are required to resolve this issue.