Pramipexole attenuates neuronal injury in Parkinson's disease by targeting miR-96 to activate BNIP3-mediated mitophagy.

BACKGROUND: Parkinson's disease is a common neurodegenerative problem. Pramipexole (PPX) plays protective role in Parkinson's disease. Nevertheless, the mechanism of PPX in Parkinson's disease-like neuronal injury is largely uncertain. METHODS: 1-methyl-4-phenylpyridinium (MPP+)-stimulated neuronal cells and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice were used as the model of Parkinson's disease. MPP+-induced neuronal injury was assessed via cell viability, lactic dehydrogenase (LDH) release and apoptosis. microRNA-96 (miR-96) and BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) abundances were examined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) or Western blotting. Mitophagy was tested by Western blotting and immunofluorescence staining. MPTP-induced neuronal injury in mice was investigated via behavioral tests and TUNEL. RESULTS: PPX alleviated MPP+-induced neuronal injury via increasing cell viability and decreasing LDH release and apoptosis. PPX reversed MPP+-induced miR-96 expression and inhibition of mitophagy. miR-96 overexpression or BNIP3 interference weakened the suppressive role of PPX in MPP+-induced neuronal injury. miR-96 targeted BNIP3 to inhibit PTEN-induced putative kinase 1 (PINK1)/Parkin signals-mediated mitophagy. miR-96 overexpression promoted MPP+-induced neuronal injury via decreasing BNIP3. PPX weakened MPTP-induced neuronal injury in mice via regulating miR-96/BNIP3-mediated mitophagy. CONCLUSION: PPX mitigated neuronal injury in MPP+-induced cells and MPTP-induced mice by activating BNIP3-mediated mitophagy via directly decreasing miR-96.

Is traumatic meniscal lesion associated with acute fracture morphology changes of tibia plateau? A series of arthroscopic analysis of 67 patients.

BACKGROUND: Computed tomography (CT) has become a routine preoperative examination for tibial plateau fractures (TPFs). Assessing the location of the fragment and intercondylar eminence fracture can provide clinicians with valuable information; however, the evaluation of traumatic meniscal lesion (TML) and arthroscopic management are controversial. AIM: To predict TML by three-dimensional skeletal anatomy changes in unilateral TPF and bilateral TPF on preoperative thin layer CT. METHODS: Acute fracture of tibial plateau patients undergoing arthroscopic surgery between December 2017 and December 2019 were included in this retrospective study. The type, zone, and location of TMLs were diagnosed based on the operation records and/or arthroscopic videos. Measurement of three-dimensional fracture morphology included the following: Frontal fragment width of plateau, sagittal fragment subsiding distance (FSD), sagittal fracture line distance, sagittal posterior tibial slope, and transversal area ratio of fragment area) on preoperative CT three-dimensional plane. The correlation of TML with skeletal values was calculated according to unicondylar TPFs and bicondylar TPFs. RESULTS: A total of 67 patients were enrolled in this study, among which 30 patients had TMLs, lateral/medial (23/7). FSD was a particularly positive factor to predict TML, with odds ratio of 2.31 (1.26-5.63). On sagittal view of CT, FSD degree of 8 mm and posterior tibial slope exceeding 11.74° implied enhanced risk of TML in bicondylar TPFs. On coronal view, once fragment width of plateau surpassed 3 cm, incidence of TML reached 100%. On transverse view, area ratio of fragment as enhanced risk of 5.5% and FSD > 4.3 mm for predicting TML were observed in unicondylar TPFs. CONCLUSION: TML can be predicted by different parameters on preoperative CT views according to unicondylar fractures and bicondylar TPFs.

Systematic analysis of long non-coding RNA and mRNA profiling using RNA sequencing in the femur and muscle of ovariectomized rats.

OBJECTIVE: To investigate the expression profile of lncRNAs in bone and skeletal muscle of ovariectomized (OVX) rats. METHODS: Six-month-old female Sprague-Dawley (SD) rats were divided into OVX group (ovariectomized, n=12) and sham group (sham-operated, n=12). After 12 weeks, RNA-seq was used to analyze the differential expression of lncRNAs and mRNAs in femur and quadriceps between two groups. Dys-regulated expression of lncRNAs was confirmed by qRT-PCR. The cis and trans-regulatory functions were analyzed to determine their function and biological processes. Lastly, GO and KEGG analyses were performed to assess the biological relevance of genes in each profile. RESULTS: A total of 17 lncRNAs and 440 mRNAs were differentially expressed in the femur. Thirteen lncRNAs and 292 mRNAs were differentially expressed in the quadriceps. qRT-PCR results were in consistent with the RNA-seq data. Among them, ENSRNOT00000090777 was found in both femur and quadriceps samples. Bioinformatics analysis found that LNC_004549 participated in the differentiation of skeletal and skeletal muscle. CONCLUSIONS: The expression profile of lncRNAs was significantly altered in femur and quadriceps of OVX rat models, which may offer new insights into pathogenesis of osteoporosis and sarcopenia and potentially provide novel therapeutic targets.

Gushukang inhibits osteocyte apoptosis and enhances BMP-2/Smads signaling pathway in ovariectomized rats.

BACKGROUND: Traditional herbal formula Gushukang (GSK) has been clinically applied to treat primary osteoporosis, which can stimulate osteoblastogenesis and improve calcium homeostasis. However, it remains unknown the mechanism that GSK against ovariectomized (OVX) induced damage. PURPOSE: The aim of this study was to investigate the effect of GSK on BMP-2/Smsds signaling pathway and osteocyte apoptosis which has been reported to play a central role in bone remodeling. STUDY DESIGN: OVX in rat was established and GSK was administered. RESULTS: BMP-2/Smsds signaling pathway was inhibited and the number of apoptotic osteocytes was increased in OVX rats. Treatment with GSK significantly enhanced BMP-2/Smsds signaling pathway by up-regulating the expression of BMP-2, p-Smad1 and p-Smad5, Osterix and Runx2, and inhibited osteocyte apoptosis by up-regulating Bcl-xl and down-regulating Bak, which were consistent with histological changes revealed by ALP, Trap and TUNEL staining. GSK treatment improved bone mass and micro-structure of trabecular bone at distal femur in OVX rats shown by BMD, micro-CT measurement and HE staining. CONCLUSION: These data suggest that GSK exhibited protective effects on promoting bone formation and precluding osteocyte apoptosis. The underlying mechanism may be attributed to its regulation on BMP-2/Smads signaling pathway and Bcl2 family.

Constipation and risk of urinary incontinence in women: a meta-analysis.

INTRODUCTION AND HYPOTHESIS: Constipation is reported to be associated with urinary incontinence. However, the reported results have been inconsistent and contradictory. To evaluate the association between constipation and urinary incontinence in women, we performed a meta-analysis. METHODS: A comprehensive search based on PubMed, EMBASE, and the Cochrane Library was performed up to July 2018 for eligible studies in relation to the influence of constipation on urinary incontinence in women. A random-effect model was used to calculate the pooled odds risk (OR) and corresponding 95% confidence interval (CI). RESULTS: A total of 16 observational studies with 35,629 participants and 6054 urinary incontinence patients were identified in the meta-analysis. Constipation was significantly associated with the risk of urinary incontinence in women (OR 2.46, 95% CI 1.79-3.38). CONCLUSIONS: This meta-analysis suggests that constipation is significantly associated with urinary incontinence risk in women. However, further well-designed, large-scale prospective studies are needed to clarify the causality.

Elevated serum CCL4/MIP-1ß levels in postmenopausal osteoporosis patients are linked with disease severity.

AIM: To investigate if the serum CC motif ligand 4 (CCL4) levels are linked to disease severity in patients with postmenopausal osteoporosis (PMOP). PATIENTS & METHODS: We enrolled 66 PMOP females, 68 postmenopausal nonosteoporotic women and 67 healthy women of childbearing age. Bone mineral densities were assessed with dual x-ray absorptiometry scans. The Oswestry disability index and the visual analog scale were employed to quantify functional ability and severity of symptoms. Serum CCL4 levels were examined with a quantitative sandwich enzyme-linked immunosorbent assay. RESULTS: We observed a significant negative correlation of CCL4 serum levels with bone mineral density. Furthermore, serum CCL4 concentrations were significantly related to the visual analog scale and Oswestry Disability Index scores. CONCLUSION: Serum CCL4 is a potential biomarker to evaluate disease severity in PMOP females.

miR­30c suppresses prostate cancer survival by targeting the ASF/SF2 splicing factor oncoprotein.

Our previous study revealed that microRNA (miR) ­30c represents a potential tumor suppressor gene, the expression of which is associated with decreased oncogenic potential in prostate cancer (PCa) cell lines. However, the functional role and underlying mechanisms of miR­30c in PCa remain to be fully elucidated. Reverse transcription­quantitative polymerase chain reaction and immunohistochemical analysis were used to detect the expression levels of alternative splicing factor/splicing factor 2 (ASF/SF2) in PCa tissues. A luciferase reporter assay was used to investigate whether ASF/SF2 may be a direct target gene of miR­30c. In addition, the effects of miR­30c on the proliferation and apoptosis of PCa cell lines were examined, following transfection with miR­30c mimics. Furthermore, correlation analysis was performed to investigate the relationship between the expression of miR­30c and ASF/SF2 and various clinicopathological parameters of patients with PCa. The present results demonstrated that PCa tissues exhibited higher levels of alternative splicing factor/splicing factor 2 (ASF/SF2), compared with normal tissues. In addition, miR­30c was revealed to targete the 3'­untranslated region of the ASF/SF2 gene, causing a decrease in the mRNA and protein levels of ASF/SF2. Furthermore, miR­30c was reported to decrease cell proliferation, increase the percentage of cells in the G1 cell cycle phase, and promote apoptosis through the inhibition of ASF/SF2. Following correlation analysis using patient samples, the expression of ASF/SF2 was revealed to be tightly correlated with the pathological stage of PCa and biochemical recurrence (BCR). In addition, patients with PCa exhibiting low expression levels of miR­30c and high expression of ASF/SF2 had significantly lower rates of BCR­free survival. In conclusion, the present study suggested that the tumor suppressor miR­30c may be involved in PCa tumorigenesis, possibly via targeting ASF/SF2. The combined analysis of the expression of ASF/SF2 and miR­30c may be a valuable tool for early prediction of BCR in patients with PCa following radical prostatectomy.

Short-stem prostheses in primary total hip arthroplasty: A meta-analysis of randomized controlled trials.

BACKGROUND: Short-stem (SS) prostheses require less resection of the femoral neck, produce a more physiological load pattern in the proximal femur, reduce stress shielding, and aid bone conservation and are, therefore, beneficial for young patients. Conventional cementless implants in total hip arthroplasty (THA) have shown excellent clinical results; however, it is unclear whether SS prostheses can obtain the same clinical and radiological outcomes. We conducted a meta-analysis of randomized controlled trials (RCTs) to evaluate whether SS prostheses are superior to conventional implants after primary THA. METHODS: We reviewed the literature published up to June 2016 from PubMed, Web of Science, and the Cochrane Library to find relevant RCTs comparing SSs and conventional stems in primary THA. Quality assessment was performed by 2 independent reviewers. The RevMan 5.3 software program of the Cochrane Collaboration was used to analyze the data. Random- or fixed-effect models were used to calculate standardized mean differences (SMDs) and 95% confidence intervals (CIs) for each comparison. RESULTS: Six RCTs involving 552 patients with 572 hips were identified. Strong evidence indicated that SS prostheses were more effective for reducing thigh pain than conventional implants (I = 46%, P = 0.002; risk ratio [RR], 95% CI 0.15, 0.04-0.49). However, there were no significant differences between the 2 groups in Harris Hip Scores (I = 0%, P = 0.84; SMD, 95% CI 0.02, -0.15-0.18), Western Ontario and McMaster Universities Osteoarthritis Index Scores (I = 0%, P = 0.35; SMD, 95% CI 0.09, -0.10-0.27), femoral offset of stem (I = 0%, P = 0.57; SMD, 95% CI 0.06, -0.16-0.29), and leg-length discrepancy (I = 79%, P = 0.88; SMD, 95% CI 0.04, -0.44-0.51). CONCLUSION: SS prostheses achieve the same clinical and radiological outcomes as conventional implants, and were superior in terms of reducing thigh pain. But whether the postoperative thigh pain applied in 2nd-generation cementless prosthesis still needs further large-scale multicenter studies with longer follow-up to confirm.

Elevated CCL2/MCP-1 Levels are Related to Disease Severity in Postmenopausal Osteoporotic Patients.

BACKGROUND: Chemokine (C-C) ligand-2 (CCL2), also named monocyte chemoattractant protein 1 (MCP-1), is an important chemotactic factor involved in a wide range of diseases. Recent studies have shown that CCL2/MCP-1 plays crucial roles in the osteoclastogenic process. The current study was performed to measure serum CCL2 levels in postmenopausal osteoporotic patients and investigate the relationship between CCL2 concentrations in serum and disease severity in postmenopausal osteoporotic patients. METHODS: A total of 62 postmenopausal osteoporotic female patients (PMOP group), 68 postmenopausal non-osteoporotic female patients (PMNOP group), and 65 healthy women of childbearing age (Control group) were enrolled in the study. The calcaneal quantitative ultrasound was utilized to conduct bone mineral density (BMD) measurements, confirmed at the left femoral neck, greater trochanter, total hip, and L1 - L4 lumbar spine by dual energy X-ray absorptiometry (DXA). Serum CCL2, TNF-α as well as IL-6 levels were measured with enzyme-linked immunosorbent assay. Estrogen-2 (E2) was measured with radioimmunoassay. The Visual Analogue Scores (VAS) was utilized to assess the extent of pain in PMOP. RESULTS: We demonstrated for the first time that CCL2 levels were increased in postmenopausal women compared with controls. We also found that elevated CCL2 levels were linked with decreased BMD and attenuated E2 concentrations. In addition, CCL2 levels were positively correlated with inflammation markers TNF-α, IL-6, and VAS scores. CONCLUSIONS: CCL2 in serum serves as a potential biomarker for reflecting disease severity in postmenopausal osteoporotic patients. Therapeutic interventions that target CCL2 and its related signaling pathways in order to delay osteoporosis development deserve further study.

[Hedgehog signaling pathway and osteoporosis].

Hedgehog signaling pathway is a conserved and important signaling pathway involved in proliferation and differentiation of many types of cells. Latest studies have found that Hedgehog signaling pathway may induce MSCs osteoblast differentiation by increasing the expression of the Runx2 and Osx and inhibit MSCs differentiate to adipocyte. Hedgehog signaling pathway may also promote osteoblast proliferation by regulating cyclin. This review summarizes the mechanism that Hedgehog signaling pathway regulates osteoblast differentiation and proliferation,and concludes that Hedgehog signaling pathway can regulate bone metabolism. It might provide new ideas for the treatment of osteoporosis.

[Effects of Gukang on bone-source alkaline phosphatase (BALP) and insulin-like growth factor-1 (IGF-1) in serum of spaying rats].

OBJECTIVE: To investigate the effects of Gukang on bone-source alkaline phosphatase (BALP) and insulin-like growth factor 1 (IGF-1) in serum of spaying rats and the mechanism of curative effect of Gukang on osteoporosis. METHODS: Sixty-eight 6-month-old SD rats were chosen and randomly divided into blank control group (22 rats with sham operation) and operation group (46 rats with spaying operation). Three months after operation, 10 rats were randomly chosen from each group and tested with bone mineral density in order to determine models of osteoporosis made. After modeling, operation group was divided into 3 sub-groups: operation model group, estrogen group and Gukang group, 12 rars in each group. Twelve rats remained in blank control group. Every group were treated through intragastric administration therapy (volume 10 ml/kg). Blank control group and operation model group were irrigated with distilled water,estrogen group with estrogen and Gukang group with Gukang. Three months after treatment, serum of all groups were collected and tested for E2, BALP and IGF-1 with ELISA. RESULTS: The concentration of serum E2, BALP in estrogen group and Gukang group were higher than operation model group, there were significant difference (P < 0.05), but no significant difference in serum E2 between estrogen group and Gukang group (P > 0.05). The concentration of serum IGF-1 in Gukang group was higher than operation model group and blank control group, there were significant difference (P < 0.05). CONCLUSION: Gukang can increase the level of E2, BALP and IGF-1 in serum of spaying rats. Thus, it can indirectly promote reproduction of osteoblasts, inhibit activity of osteoclasts and promote bone formation.