The polymorphism of SMAD3 rs1065080 is associated with increased risk for knee osteoarthritis.

The mechanism of knee osteoarthritis (OA) is still not clearly elucidated. SMAD3 gene polymorphisms are considered to play a vital role in OA pathogenesis. We thus investigated the relationship of SMAD3 rs1065080 gene polymorphism and susceptibility to knee osteoarthritis in a Chinese Han population. A total of 237 patients and 142 healthy control participants were enrolled in a case-control study. DNA was extracted from peripheral blood samples and genotyped by using the Mass-ARRAY method. Our results revealed that there was a significant difference between patients and healthy controls in the genotype of A and G (p = 0.019); those with a GG genotype had a significant increase in OA risk (OR 2.881, 95% CI 1.993-7.353, p = 0.025). In addition, logistic regression analysis showed that the recessive genetic model decreased OA morbidity (OR 0.648, 95% CI 0.416-0.911, p = 0.046). In conclusion, the GG genotype of rs1065080 was associated with a higher risk of OA and the recessive genetic model decreased the risk of OA.

Total cholesterol to high-density lipoprotein cholesterol ratio is a significant predictor of nonalcoholic fatty liver: Jinchang cohort study.

BACKGROUND: Some studies found out that TC/HDL-C ratio is a predictor of Cardiovascular disease (CVD) and Nonalcoholic fatty liver (NAFLD) is related to CVD. And some researches have already studied that Apolipoprotein B to Apolipoprotein A1 ratio (ApoB/ApoA1) and Triglyceride to High-density lipoprotein cholesterol ratio (TG/HDL-C) were both related with CVD and NAFLD, but few studied the association between TC/HDL-C ratio and NAFLD. So, we suspected the ratio was also related to NAFLD. The research aims to study the predictive value of TC/HDL-C to NAFLD and to help the early detection of NAFLD. METHODS: Based on the Jinchang Cohort, the study contained 32,121 participants. We assessed the incidence of NAFLD by the quartiles of TC, HDL-C and TC/HDL-C. Then, the does-response relationship between these indicators and the risk of NAFLD was obtained. Finally, the receiver operator characteristic curve (ROC) was applied to decide the predictive value of TC/HDL-C. RESULTS: Among the study participants, the cumulative incidence of NAFLD was 6.30% and the rate of dyslipidemia was 40.37%. The biochemical indicators of NAFLD had a difference with general population. The incidence of NAFLD raised with the quartiles of TC, TG and LDL-C raising, while decreased with the HDL-C' quartiles raising. After controlling confounding factors, TC and TC/HD-C had a positive relationship with NAFLD, while HDL-C had the opposite. Finally, the ROC analysis showed the area under the curve (AUC) of TC/HDL-C (0.645) was greater than TC (0.554), HDL-C (0.627) and Apolipoprotein B to Apolipoprotein A1 (ApoB/ApoA1) (0.613). CONCLUSIONS: The TC/HDL-C ratio has significant predictive value to NAFLD.

Yin-chen Wu-ling powder alleviate cholestatic liver disease: Network pharmacological analysis and experimental validation.

BACKGROUND: Yin-chen Wu-ling Powder (YWP) has potential therapeutic effects on cholestatic liver disease (CLD), however, its active compounds and conceivable mechanism are as yet indistinct. METHODS: The network pharmacology and gene function annotation examined the multiple active ingredients, potential targets, and possible mechanisms of YWP in CLD treatment. Then the molecular docking reassured the reliability of the core compounds including the key genes and farnesoid X receptor (FXR). Finally, The Mdr2-/- mice were used to test the effect and mechanism of YWP against CLD. RESULTS: The network analysis identified nine main active ingredients, including quercetin, capillarisin, eupalitin, isorhamnetin, skrofulein, genkwanin, cerevisterol, gederagenin, and sitosterol. The PPI network predicted the ten hub genes involved were AKT1, MAPK1, MAPK14, IL6, RXRA, ESR1, IL10, NCOA1, CAV1, and EGFR. The KEGG and GO analysis showed that YWP might contribute to CLD treatment through the PI3K/Akt and MAKP signalings to manage pathological reactions, for instance, inflammatory responses. The molecular docking displayed a functional similarity among the core compounds with ursodeoxycholic acid (UDCA) and Obeticholic acid (OCA) on the effects on AKT1, MAPK1, MAPK14, RXRA, and ESR, and the affinity to FXR. In addition, the YWP could significantly attenuate hepatic injury and improve inflammatory response in Mdr2-/- mice. The mechanism exploration showed that YWP mainly decreased inflammatory response by inhibiting AKT/P38MAPK signaling. CONCLUSION: This study firstly revealed the multiple active ingredients, potential targets, and possible mechanism of YWP to treat CLD based on network pharmacology Analysis and molecular docking. YWP could alleviate cholestasis in Mdr2-/- mice by impairing inflammation via inhibiting AKT/P38MAPK Signaling.

[Reliability of tibial anterior crest as the anatomical reference of rotating alignment for tibial component in total knee arthroplasty].

OBJECTIVE: This study aimed to research whether anterior tibial crest is a reliable anatomical reference for rotational alignment of tibial component in TKA. METHODS: The study included 122 patients who underwent computed tomography angiography (CTA) examination for unilateral lower extremity trauma with normal contralateral lower extremities, including 89 males and 33 females, with an average age of(51.4±16.4) years old(ranged 18 to 81 years old). Picture archiving and communication system (PACS) was used to mark 11 lines including the surgical epicondylar axis (SEA) connecting the most prominent points of the lateral epicondyle and the deepest point of the sulcus on the medial epicondyle of the femur, axis of medial border of patellar tendon (MEPT)connecting the middle of the posterior cruciate ligament (PCL) and medial border of the patellar tendon at the level of a standard tibial cut from 8 mm distal of the lateral tibial joint surface, transverse axis of tibia (TAT) at the level of a standard tibial cut from 8 mm distal of the lateral tibial joint surface, Akagi line connecting the projected middle of the PCL and medial border of the patellar tendon at the tibial attachment, the axis of the medial 1/3 of patellar tendon(M1/3) connecting the projected middle of PCL and the medial 1/3 of the patellar tendon at the patellar tendon attachment level, Insall line connecting the projected middle of the PCL and the medial 1/3 of tibial tubercle, the axis of medial border of tibial tubercle (MBTT) connecting the projected middle of the PCL and medial border of tibial tubercle, as well as the axis of the proximal anterior tibial crest (PATC), axis 1 of the middle anterior tibial crest (MATC1), axis 2 of the middle anterior tibial crest (MATC2) and the axis of the distal anterior tibial crest (DATC) which were marked by connecting the 4 equidistant points on the sharp anterior tibial crest and the projected middle of the PCL. The angles between TAT and SEA as well as the angles between other axes and the perpendicular to SEA were measured. Pairwise differences among the 10 tibial axes were examined using One-Way ANOVA and paired t-test. RESULTS: The angles between the axes of MEPT, Akagi line, M1/3, Insall line, MBTT, PATC, MATC1, MATC2, DATC and the perpendicular to SEA were (-1.6 ±4.5)° , (1.4 ±5.0)° , (10.2±5.1)°, (11.9±5.4)°, (3.6±4.8)°, (12.0±6.9)°, (7.2±8.6)°, (7.1±10.4)°, (6.6±13.5)°, respectively. The angle between TAT and SEA was (4.1±5.3)°. MEPT was external rotation compared to SEA. M1/3, Insall line and PATC were significantly greater than Akagi line, MBTT, TAT (P<0.001). MATC1, MATC2 and DATC were also significantly greater than Akagi line, MBTT axis and TAT (P<0.001). However, MATC1, MATC2 and DATC were also significantly less than M1/3 axis, Insall line and PATC(P<0.01). There were no significant statistical differences between MATC1, MATC2 and DATC(P>0.05). CONCLUSION: The middle tibial anterior crest can be used as a reference for rotational alignment of tibial component in TKA, and its reliability is better than Insall line, but worse than Akagi line, TAT and MBTT.

Protocol to study the effects of Traditional Chinese Medicine on patients with coronary heart disease showing phlegm-heat-stasis symptom pattern.

OBJECTIVE: To describe a protocol to assess the effects of Traditional Chinese Medicine (TCM) on patients with coronary heart disease (CHD) showing symptoms of phlegm-heat-stasis symptom pattern. METHODS: This is a single-blind randomized controlled trial that will be conducted in the First Teaching Hospital of Tianjin University of TCM and 60 patients with CHD showing phlegm-heat-stasis symptom pattern will be included. Patients will be randomly divided into either a treatment group (Qingre Huatan formulae + Western Medicine) or to a control group (conventional Western Medicine only) for 7-14 d. Primary patient outcomes will be vascular endothelial function and quality of life. Measurement data will be expressed as mean ± standard deviation using t-test analysis or repeated-measure variance analysis. Enumeration data will be expressed by cases and percentages, using χ2 analysis, and rank sum test will be used for ranked data. RESULTS: This study further verified the effectiveness and safety of Qingre Huatan formulae for the phlegm-heat-stasis syndrome pattern of CHD on the basis of previous studies on the characteristics of syndromes and medication rules. DISCUSSION: Phlegm-heat-stasis symptom pattern has become a common manifestation in CHD. Standardized Western medications together with TCM have been extensively used in China and have developed into a comprehensive treatment model. Our trial will help formulate recommendations for symptom maintenance and provide clinical evidence for the application of TCM for patients with CHD showing phlegm-heat-stasis symptom pattern.

Proangiogenic functions of osteopontin-derived synthetic peptide RSKSKKFRR in endothelial cells and postischemic brain.

OBJECTIVE: The aim of this study was to investigate the potential therapeutic effects of a newly discovered osteopontin-derived synthetic peptide "RSKKFRR" in a rat model of ischemic stroke. METHODS: A total of 24 male SD rats were randomly divided into three groups. The model of ischemic stroke was made up of the middle cerebral artery occlusion (MACO). The rats were divided into sham operation group (Sham), control group (MACO + PBS) and treatment group (MACO + OPNpt9), eight rats in each group. In the control group and the treatment group, PBS or OPNpt9 was injected into the nasal cavity after MACO once a day, and the area of new blood vessels and the recovery of nerve function were observed 14 days later. Whether the proliferation, migration and tube formation of HUVECs were promoted by OPNpt9 was tested. The expression levels of related proangiogenic factors were also detected. RESULTS: OPNpt9 was found to contribute to cerebral microvascular remodeling and neurological improvement in ischemic rats while promoting endothelial cell migration, proliferation and tube formation in vitro. These effects were mediated by activation of the p-ERK/MMP-9/VEGF pathway. CONCLUSION: In conclusion, OPNpt9 promotes angiogenesis and neurological recovery after ischemic stroke.

Identification of pivotal genes and pathways in the synovial tissue of patients with rheumatoid arthritis and osteoarthritis through integrated bioinformatic analysis.

Rheumatoid arthritis (RA) and osteoarthritis (OA) are the two most common debilitating joint disorders and although both share similar clinical manifestations, the pathogenesis of each is different and remains relatively unclear. The present study aimed to use bioinformatic analysis to identify pivotal genes and pathways involved in the pathogenesis of RA. Microarray datasets from patients with RA and OA were obtained from the Gene Expression Omnibus (GEO) database and differentially expressed genes (DEGs) were identified using GEO2R software; Gene Ontology analysis and pathway enrichment were analyzed using the Database for Annotation, Visualization and Integrated Discovery and the Kyoto Encylopedia for Genes and Genomes, respectively; and protein­protein interaction networks of DEGs were constructed using the Search Tool for the Retrieval of Interacting Genes database, and module analysis and pathway crosstalk of the PPI network was visualized using plugins of Cytoscape. In addition, the prediction of target mRNAs for differentially expressed microRNAs (DEMs) was performing using the starBase database and the identified pivotal genes were verified using reverse­transcription quantitative PCR in synovial tissue from patients with RA. A total of 566 DEGs were identified in GSE55457, GSE55235 while 23 DEMs were identified in the GSE72564 dataset. Upregulated DEGs were found to be mostly enriched in the 'Cytokine­cytokine receptor interaction' pathway, whereas downregulated DEGs were discovered to be enriched in the 'PPAR signaling pathway'. The top 25 DEGs were mostly enriched in the 'Chemokine signaling pathway'. In addition, six of the miRNA target genes were selected as potential biomarkers and a total of 24 genes were selected as potential hub genes. Experimental validation demonstrated that the expression levels of Cytotoxic T­Lymphocyte Associated Protein 4 (CTLA4), Zeta­chain­associated protein kinase 70 (ZAP70) and LCK proto­oncogene (LCK) were significantly increased, whereas HGF expression levels were decreased in RA synovial tissue. In conclusion, these findings suggest that the identified DEGs and pivotal genes in the present study may further enhance our knowledge of the underlying pathways in the pathogenesis of RA. These genes may also serve as diagnostic biomarkers and therapeutic targets for RA; however, further experimental validation is necessary following the bioinformatic analysis to determine our conclusions.

The association between non-motor symptoms in Parkinson's disease and age at onset.

OBJECTIVE: Age at onset is likely to be related to a wide range of problems in Parkinson's disease (PD), including cardinal motor features, motor complications and non-motor symptoms (NMS). This study investigated the effect of the age at onset on NMS. METHODS: Two hundred and thirty patients were examined and classified into one of three groups based on age at onset: early onset PD (EOPD) group (<45 years), middle-age onset group (45-64 years) and old-age onset group (≥65 years). The trends relating to NMS were compared across the three groups. The EOPD and old-age onset groups were separately studied to determine their association to the appearance of non-motor features using logistic regression analysis. RESULTS: There were upward trends in the occurrence of dribbling (P=0.009; all P values are stated for trend), impaired taste/smelling (P=0.016), constipation (P=0.006), urinary urgency (P=0.002), nocturia (P=0.018), hallucinations (P=0.016) and acting out during dreams (P=0.011) with the increase of age at onset. Older age at onset is an independent risk factor for dementia (OR=8.42, CI 3.16-22.44), dribbling (OR=4.14, CI 1.93-8.87), impaired taste/smelling (OR=2.23, CI 1.20-4.13), constipation (OR=3.42, CI 1.88-6.24), incomplete bowel emptying (OR=2.23, CI 1.19-4.20), urinary urgency (OR=2.58 CI 1.46-4.57), nocturia (OR=2.65, CI 1.49-4.71), hallucinations (OR=5.32, CI 1.78-15.97), dizziness (OR=3.03, CI 1.59-5.79), falling (OR=3.60, CI 1.67-7.77), insomnia (OR=2.29, CI 1.28-4.11), intense vivid dreaming (OR=2.10, CI 1.21-3.66) and acting out during dreams (OR=2.23, CI 1.24-4.01). CONCLUSIONS: PD patients with different ages at onset present clinically different symptoms in terms of NMS. Old-age onset PD is characterized by more olfactory and sensory symptoms, autonomic symptoms, sleep disorders, dementia and psychosis compared to EOPD.

Kaempferol protects against doxorubicin-induced cardiotoxicity in vivo and in vitro.

The long-term clinical usefulness of doxorubicin (DOX), an anthracycline with potent antitumor activity, is limited by DOX-induced cardiotoxicity. Kaempferol, one of the most common dietary flavonoids, is known to have anti-apoptotic, anti-oxidative, and anti-inflammatory properties. The current study aimed to investigate the possible protective effect of kaempferol against DOX-induced cardiotoxicity and the underlying mechanisms. Rats were intraperitoneally (i.p.) treated with DOX (3 mg/kg) every other day for a cumulative dose of 9 mg/kg. After 28 days, DOX caused retarded body and heart growth, oxidative stress, apoptotic damage, mitochondrial dysfunction, and Bcl-2 expression disturbance. In contrast, kaempferol pretreatment (10 mg/kg i.p. before DOX administration) attenuated the DOX-induced apoptotic damage in heart tissues. In vitro studies also indicated that kaempferol may have used the mitochondrion-dependent pathway to counteract the DOX-induced cardiotoxicity. This counteraction was achieved by inhibiting p53 expression and its binding to the promoter region of the Bax proapoptotic gene, but not to the Bcl-2 antiapoptotic gene. Kaempferol also effectively suppressed DOX-induced extracellular signal-regulated kinase (ERK) 1/2 activation, but had no effect on p38 and JNK. Therefore, kaempferol protected against DOX-induced cardiotoxicity, at least, partially, by inhibiting the activation of p53-mediated, mitochondrion-dependent apoptotic signaling, and by being involved in an ERK-dependent mitogen-activated protein kinase pathway. These findings elucidated the potential of kaempferol as a promising reagent for treating DOX-induced cardiotoxicity, and may have implications in the long-term clinical usefulness of DOX.