Meso-Hannokinol inhibits breast cancer bone metastasis via the ROS/JNK/ZEB1 axis.

Distal metastases from breast cancer, especially bone metastases, are extremely common in the late stages of the disease and are associated with a poor prognosis. EMT is a biomarker of the early process of bone metastasis, and MMP-9 and MMP-13 are important osteoclastic activators. Previously, we found that meso-Hannokinol (HA) could significantly inhibit EMT and MMP-9 and MMP-13 expressions in breast cancer cells. On this basis, we further explored the role of HA in breast cancer bone metastasis. In vivo, we established a breast cancer bone metastasis model by intracardially injecting breast cancer cells. Intraperitoneal injections of HA significantly reduced breast cancer cell metastasis to the leg bone in mice and osteolytic lesions caused by breast cancer. In vitro, HA inhibited the migration and invasion of breast cancer cells and suppressed the expressions of EMT, MMP-9, MMP-13, and other osteoclastic activators. HA inhibited EMT and MMP-9 by activating the ROS/JNK pathway as demonstrated by siJNK and SP600125 inhibition of JNK phosphorylation and NAC scavenging of ROS accumulation. Moreover, HA promoted bone formation and inhibited bone resorption in vitro. In conclusion, our findings suggest that HA may be an excellent candidate for treating breast cancer bone metastasis.

Idiopathic Sudden Sensorineural Hearing Loss in Patients with Obstructive Sleep Apnea.

PURPOSE: Obstructive sleep apnea (OSA) is characterized by recurring hypoxic-apneic events during sleep, and labyrinthine vascular compromise is a pathophysiologic hallmark of idiopathic sudden sensorineural hearing loss (ISSNHL). Some reports have discussed the relationship between OSA and hearing impairment; however, few have examined hearing prognosis in OSA and patients without OSA with ISSNHL. We aimed to investigate clinical manifestations of ISSNHL in patients with OSA, including severity of hearing loss and response to treatment. PATIENTS AND METHODS: A case-control study was conducted by extracting data from the sleep center and cochlea center databases of the Chang Gung Memorial Hospital. A retrospective chart review was performed to include confirmed adult OSA patients diagnosed with unilateral ISSNHL. Age and sex-matched patients without OSA with ISSNHL were enrolled as controls. Pure-tone average (PTA) thresholds were measured at specific frequencies. Changes in PTA before and after standard treatment with oral prednisolone (1mg/kg/day for 5 days, then tapered) and between participants with OSA and without OSA were compared. Standard treatment was given to all ISSNHL patients. RESULTS: Twenty-eight out of 8500 (0.33%) OSA patients experienced subsequent ISSNHL in 9 years. Patients with OSA (n=28) had poorer high-frequency perception in the unaffected ear than the patients without OSA (n=120), although the difference was not significant. Hearing in the affected ear among patients with OSA was comparable to that patients without OSA at individual frequencies and average, suggesting no difference in hearing loss in the affected ear between the two groups. In terms of high-frequencies (4000 and 8000 Hz) perception, patients with OSA had significantly poorer responses to steroid treatment than patients without OSA. CONCLUSION: ISSNHL may be one of the auditory complications associated with OSA. Patients with OSA had poorer prednisolone related hearing improvement in high frequencies than patients without OSA. Despite study limitations, OSA-related hypoxia and snoring noise is hazardous to hearing and standard treatments with CPAP is suggested in OSA patients for both holistic and auditory health.

Avicularin suppresses cartilage extracellular matrix degradation and inflammation via TRAF6/MAPK activation.

BACKGROUND: Osteoarthritis (OA) is an intractable degenerative disease of the whole joint, which is characterized by synovitis inflammation, cartilage damage, and chronic pain. Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) performs an important role in OA. PURPOSE: We aim to investigate avicularin to protect cartilage extracellular matrix degradation (ECM) and suppresses inflammation both in rat and human chondrocytes. METHODS: 5-Ethynyl-2'-deoxyuridine (EdU) staining, Quantitative real-time PCR, TRAF6 plasmid transfection, Western blot, Measurement of nitric oxide (NO), ROS detection and Immunofluorescence were utilized in vitro. micro-CT scanning, Safranin O-Fast Green, toluidine blue and immunohistochemistry staining were performed in vivo. RESULTS: In vitro, avicularin attenuates the degradation of ECM and inflammation, which could inhibit the activation of TRAF6/MAPK pathway via targeting TRAF6. Increased MMP3 and MMP13 expressions and decreased Aggrecan and Collagen Ⅱ levels were observed in anterior cruciate ligament transection (ACLT) induced osteoarthritic rats. Interestingly, intra-articular injection of avicularin attenuates this phenomenon. CONCLUSIONS: Taken together, our results indicate that avicularin suppresses cartilage extracellular matrix degradation and inflammation via TRAF6/MAPK activation by targeting TRAF6. These observations identify TRAF6 as a relevant drug target, and avicularin may as a potential therapeutic agent in osteoarthritis.

Susceptibility of bacterial endophthalmitis isolates to vancomycin, ceftazidime, and amikacin.

Bacterial endophthalmitis is a rare intraocular infection, and prompt administration of intravitreal antibiotics is crucial for preventing severe vision loss. The retrospective study is to investigate the in vitro susceptibility to the antibiotics vancomycin, amikacin, and ceftazidime of bacterial endophthalmitis isolates in specimens at a tertiary referral center from January 1996 to April 2019 in Taiwan. Overall, 450 (49.9%) isolates were Gram positive, 447 (49.6%) were Gram negative, and 4 (0.4%) were Gram variable. In Gram-positive isolates, coagulase-negative staphylococci were the most commonly cultured bacteria (158, 35.1%), followed by Streptococci (100, 22.2%), Enterococci (75, 16.7%), and Staphylococcus aureus (70, 15.6%). In Gram-negative isolates, they were Klebsiella pneumoniae (166, 37.1%) and Pseudomonas aeruginosa (131, 29.3%). All Gram-positive organisms were susceptible to vancomycin, with the exception of one Enterococcus faecium isolate (1/450, 0.2%). Of the Gram-negative isolates, 96.9% and 93.7% were susceptible to ceftazidime and amikacin, respectively. Nine isolates (9/447, 2.0%) were multidrug-resistant Gram-negative bacteria, comprising K. pneumoniae (4/164, 2.4%), Acinetobacter baumannii (2/3, 67%), and Stenotrophomonas maltophilia (3/18, 17%). In conclusion, in vitro susceptibility testing revealed that vancomycin remains the suitable antibiotic treatment for Gram-positive endophthalmitis. Ceftazidime and amikacin provide approximately the same degree of Gram-negative coverage. Multidrug-resistant bacterial endophthalmitis was uncommon.

Geniposide downregulates the VEGF/SphK1/S1P pathway and alleviates angiogenesis in rheumatoid arthritis in vivo and in vitro.

The VEGF/SphK1/S1P pathway is closely related to angiogenesis in rheumatoid arthritis (RA), but the precise underlying mechanisms are unclear at present. Here, we explored the involvement of the VEGF/SphK1/S1P cascade in RA models and determined the effects of GE intervention. Our results showed abnormal expression of proteins related to this pathway in RA synovial tissue. Treatment with GE effectively regulated the signal axis, inhibited angiogenesis, and alleviated RA symptoms. In vitro, TNF-ɑ enhanced the VEGF/SphK1/S1P pathway in a co-culture model of fibroblast-like synoviocytes (FLS) and vascular endothelial cells (VEC). GE induced downregulation of VEGF in FLS, restored the dynamic balance of pro-/antiangiogenic factors, and suppressed SphK1/S1P signaling in VEC, resulting in lower proliferation activity, migration ability, tube formation ability, and S1P secretion ability of VEC cells. Additionally, SphK1-specific small interfering RNA (siRNA) blocked the VEGF/SphK1/S1P cascade, which can effectively alleviate the stimulatory effect of FLS on VEC and further enhanced the therapeutic effect of GE. Taken together, our results demonstrate that GE suppresses the VEGF/SphK1/S1P pathway and alleviates the stimulation of VEC by FLS, thereby preventing angiogenesis and promoting therapeutic effects against RA.

Streptococcus pneumoniae endophthalmitis: clinical settings, antibiotic susceptibility, and visual outcomes.

Streptococcus pneumoniae endophthalmitis is clinically more severe, more difficult to treat, and carry a higher risk of vision loss, evisceration, or enucleation. This study is to investigate the clinical settings, antibiotic susceptibility, and visual outcomes of S. pneumoniae endophthalmitis at a tertiary referral center in Taiwan. S. pneumoniae endophthalmitis was diagnosed in 38 eyes of 38 patients. The main clinical features were postcataract endophthalmitis (n = 13, 34%) and endophthalmitis associated with corneal ulcer (n = 12, 32%), trauma (n = 6, 16%), endogenous etiology (n = 4, 11%), trabeculectomy (n = 2, 5%), and pterygium excision-related scleral ulcer (n = 1, 3%). Presenting visual acuity ranged from counting fingers to no light perception. Pars plana vitrectomy with intravitreal antibiotics was performed in 17 eyes (39%) in primary or secondary treatments. S. pneumoniae isolates were susceptible to vancomycin (38/38, 100%), penicillin (37/38, 97%), ceftriaxone (37/38, 97%), cefuroxime (12/15, 80%), levofloxacin (13/15 ,87%), and moxifloxacin (15/17, 88%). Final visual acuity was better than 20/400 in 3 of 38 eyes (8%), 5/200 to hand motions in 3 eyes (8%), and light perception to no light perception in 32 eyes (84%). Ten eyes (26%) underwent evisceration or enucleation. Although S. pneumoniae isolates were susceptible to vancomycin, S. pneumoniae endophthalmitis had a very poor visual prognosis.

Rare ocular features in a case of Kabuki syndrome (Niikawa-Kuroki syndrome).

BACKGROUND: Kabuki syndrome is a multi-system disorder with peculiar facial features, and ophthalmic abnormalities are frequently involved. This case report of a child with Kabuki syndrome describes two new previously unreported ophthalmic conditions. CASE PRESENTATION: A 3-year-old Taiwanese boy with Kabuki syndrome had a short stature, spinal dysraphism, intellectual disability and typical facial features. Ophthalmic findings which have been previously reported in the literature and in this patient, included ptosis, esotropia, coloboma of the iris, retina, choroid and optic disc, and microcornea. The newly identified ophthalmic features in this patient included colobomatous microphthalmos and a dysplastic and elevated disc without central cupping. The genetic analysis identified an MLL2 gene mutation. CONCLUSION: The presentations of a dysplastic disc and colobomatous microphthalmia are rarely reported in patients with Kabuki syndrome, but these ophthalmic abnormalities may affect vision. Detailed ophthalmic evaluations in children with Kabuki syndrome are advised.

[Removal of heavy metals from extract of Angelica sinensis by EDTA-modified chitosan magnetic adsorbent].

The concentrations of heavy metals in the extracting solutions of traditional Chinese medicine are usually very low. Furthermore, a vast number of organic components contained in the extracting solutions would be able to coordinate with heavy metals, which might lead to great difficulty in high efficient removal of them from the extracting solutions. This paper was focused on the removal of heavy metals of low concentrations from the extracting solution of Angelica sinensis by applying an EDTA-modified chitosan magnetic adsorbent (EDTA-modified chitosan/SiO2/Fe3O4, abbreviated as EDCMS). The results showed that EDCMS exhibited high efficiency for the removal of heavy metals, such as Cu, Cd and Pb, e.g. the removal percentage of Cd and Pb reached 90% and 94.7%, respectively. Besides, some amounts of other heavy metals like Zn and Mn were also removed by EDCMS. In addition, the total solid contents, the amount of ferulic acid and the HPLC fingerprints of the extracting solution were not changed significantly during the heavy metal removal process. These results indicate that EDCMS may act as an applicable and efficient candidate for the removal of heavy metals from the extracting solution of A. sinensis.

[Comparison of pelvic transarterial chemoembolization with lipiodol ultra-fluid carboplatin and transarterial carboplatin through experiment in dogs].

BACKGROUND & OBJECTIVE: Transarterial chemoembolization, based on transarterial chemotherapy, is a new treatment for malignant neoplasms. This study was to investigate distribution of platinum (Pt) in blood and uterine tissue after infusing different carboplatin arterially. METHODS: Fourteen female dogs were randomly divided into 2 groups: embolizational group (group A, 7 dogs),and chemotherapy group (group B, 7 dogs). In group A, carboplatin (12 mg/kg), mingled with lipidol ultra-fluid (0.2 ml/kg), was injected into dogs' iliac arteries. In group B, carboplatin (12 mg/kg), dissolved in 5% glucose, was injected into the same arteries. The uterine tissues and blood samples were collected at different time points, concentrations of Pt in samples were measured by atomic absorption method. RESULTS: Peak concentration of Pt in uterine tissues of group A was (215.0+/-17.6) microg/g, that of group B was (211.3+/-40.1) microg/g (P >0.05), the peak appeared at 0 min in both groups. Area under concentration-time curve (AUC) of Pt in tissues of group A was (13.9+/-3.9) mg x min x g(-1), significantly larger than that of group B (5.9+/-0.6) mg x min x g(-1). Peak concentration of Pt in plasma of group A was (8.7+/-12.5) microg/g, that of group B was (16.7+/-3.6) microg/g. AUC(0-240 min) was (0.5+/-0.1) mg x min x g(-1) in group A,and (1.2+/-0.4) mg x min x g(-1) in group B (P< 0.05). CONCLUSION: Compared with arterial chemotherapy, arterial chemo- embolization may result in higher Pt concentration in local area, and lower Pt concentration in plasma, it may reduce the systemic toxicities, and enhance local effect on tumor.