Publications by authors named "Chunmei Zhao"

92 Publications

Occipital Nerve Blockade for the Treatment of Occipital Neuralgia-Like Acute Postcraniotomy Headache: A Retrospective Study.

Pain Res Manag 2021 19;2021:5572121. Epub 2021 Apr 19.

Department of Pain Management, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China.

Objective: The therapeutic effectiveness and safety of occipital nerve blockade (ONB) on occipital neuralgia- (ON-) like acute postcraniotomy headache (ON-APCH) was evaluated.

Background: Persistent occipital neuralgia is a subclassification of chronic postcraniotomy headache and has been investigated sporadically in previous publications. The long-lasting neuralgic pain significantly impairs postoperative recovery and quality of life. However, little is known regarding ON-APCH and its management.

Methods: All data were retrospectively acquired from consultation records and electronic institutional medical documents. Forty-one patients, who developed drug-resistant ON-APCH after elective craniotomy and received ONB with lidocaine for diagnoses, were included in this study, all of whom were treated using dexamethasone and lidocaine. Pain intensity and ONB correlated complications and side effects were collected and analyzed at three different time points: before ONB, at 1 day after ONB, and at discharge.

Results: Nineteen males and twenty-two females aged 49.6 ± 15.2 years were diagnosed with drug-resistant ON-APCH. The mean NRS was 8.0 ± 0.9 before ONB, which later significantly decreased to 2.1 ± 1.4 and 1.6 ± 0.6 at 1 day after ONB and on discharge, respectively. At 1 month after ONB, thirty patients (73%) obtained complete pain relief without medication. At 3 months after ONB, only two (5%) patients had to continue oral medications to maintain pain relief. No adverse effects or complications were observed immediately after, or within 3 months, of the nerve blockade.

Conclusions: For drug-resistant ON-APCH, early occipital nerve blockade with dexamethasone and lidocaine is an effective and safe technique, which provides adequate pain relief and may prevent further development of persistent presentation of refractory ON.
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http://dx.doi.org/10.1155/2021/5572121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075680PMC
July 2021

Pre-Emptive Incision-Site Infiltration with Ropivacaine Plus Dexamethasone for Postoperative Pain After Supratentorial Craniotomy: A Prospective Randomized Controlled Trial.

J Pain Res 2021 19;14:1071-1082. Epub 2021 Apr 19.

Department of Pain Management, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, People's Republic of China.

Background: Incision-site infiltration with local anesthetics prevents pain on incision site, but pain relief is limited to the first few postoperative hours. Dexamethasone as an adjuvant to local infiltration successfully achieves better postoperative pain relief; however, this has not been studied in craniotomy patients yet.

Study Design And Methods: This is a prospective, single-center, blinded, randomized, controlled trial included patients aged between 18 and 64 years, ASA physical status of I-II, scheduled for elective supratentorial tumor craniotomy under general anesthesia. We screened patients for enrollment from April 4, 2019 through August 15, 2019. The final study visit of the last patient was conducted on February 13, 2020. We randomly assigned eligible participants (1:1) to either the dexamethasone group who received incision-site infiltration of 0.5% ropivacaine plus 0.033% dexamethasone (N=70) or the control group who received 0.5% ropivacaine alone (N=70). Primary outcome was the cumulative sufentanil consumption (μg) within 48 hours postoperatively. Primary analysis was performed based on the modified intention-to-treat (MITT) principle.

Results: Baseline characteristics were similar between the groups (p>0.05). Sufentanil consumption during the first 48 hours postoperatively was 29.0 (10.7) μg in the dexamethasone group and 38.3 (13.7) μg in the control group (mean difference -9.3, 95% CI -13.4 to -5.1; p<0.001). There was no serious adverse effect directly associated with incision-site infiltration or local dexamethasone use.

Conclusion: The addition of dexamethasone to pre-emptive incision-site infiltration with the local anesthetic can reduce about 27% of opioids consumption and the postoperative pain scores within 72 hours after craniotomy.

Trial Registration: ClinicalTrials.Gov (NCT03618264).
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http://dx.doi.org/10.2147/JPR.S300943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064677PMC
April 2021

A Systematic Approach To Promote Environmental Engineering Students' Learning in Environmental Molecular Microbiology.

J Microbiol Biol Educ 2021 15;22(1). Epub 2021 Mar 15.

Department of Biological Sciences, GRIL-TOXEN, University of Quebec in Montreal, Montreal, Canada H3C 3P8.

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http://dx.doi.org/10.1128/jmbe.v22i1.1917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976779PMC
March 2021

Dexamethasone as a ropivacaine adjuvant to pre-emptive incision-site infiltration analgesia in pediatric craniotomy patients: A prospective, multicenter, randomized, double-blind, controlled trial.

Paediatr Anaesth 2021 Jun 23;31(6):665-675. Epub 2021 Mar 23.

Department of Pain Management, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Background: Dexamethasone added to incision-site infiltration has been routinely used to reduce pain after tonsillectomy in children. However, this has not been studied in pediatric craniotomy patients yet. We hypothesized that incision-site infiltration with a combination of ropivacaine and dexamethasone might provide superior analgesia to ropivacaine alone in pediatric craniotomy patients.

Methods: In this multicenter, double-blind, randomized, controlled trial, children aged 2-12 years, scheduled for craniotomy, were prospectively enrolled at two study centers, from September 2, 2019, to July 5, 2020. Eighty children were randomly assigned (1:1) to either ropivacaine plus dexamethasone group who received pre-emptive incision-site infiltration with 0.2% ropivacaine plus 0.025% dexamethasone, or ropivacaine group who received 0.2% ropivacaine alone. Primary outcome was the modified Children's Hospital of Eastern Ontario Pain Scale (mCHEOPS) at 24 h postoperatively. Primary analysis was performed using the modified intention-to-treat principle.

Results: Pre-emptive incision-site infiltration with ropivacaine plus dexamethasone had a reduced pain score of 2.0, compared with the pain score of 2.9 in the ropivacaine group, at 24 h postoperatively (mean difference -0.9, 95% confidence interval [CI], -1.7 to -0.2; p = .019). Estimated median of the time of first rescue analgesic demand was 24 h in the ropivacaine plus dexamethasone group and 8.5 h in the ropivacaine group [hazard ratio 0.43, 95% CI 0.24 to 0.08; Log-rank p = .0025]. No adverse events related to incision-site infiltration with dexamethasone were observed in this study.

Discussion: Dexamethsone reduces the local production of pro-inflammatory factors after tissue damage and as a ropivacaine adjuvant for incision-site infiltration reduced the pain scores by 31% at 24 h postoperatively. The results were similar to several prior studies on to tonsillectomy patients. However, this changes on pain scores might has limited clinical significance.

Conclusions: The addition of dexamethasone to ropivacaine for preoperative incision-site infiltration has better postoperative analgesic effect than ropivacaine alone in pediatric craniotomy patients.
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http://dx.doi.org/10.1111/pan.14178DOI Listing
June 2021

Clinical characteristics, rates of blindness, and geographic features of PACD in China.

Can J Ophthalmol 2021 Jan 21. Epub 2021 Jan 21.

The Eye Hospital of Wenzhou Medical University, Wenzhou, China.

Objective: To analyze the rates of blindness with the demographics and clinical characteristics of patients with primary angle-closure disease (PACD) to provide a comprehensive epidemiologic reference in China.

Methods: A retrospective analysis was conducted in the Chinese Glaucoma Study Consortium database, which is a national multicenter glaucoma research alliance of 111 hospitals participating between December 21, 2015 and September 9, 2018. The diagnosis of PACD was made by qualified physicians through examination. Comparison of sex, age, family history, subtypes of PACD, and blindness were analyzed.

Results: A total of 5762 glaucoma patients were included, of which 4588 (79.6%) had PACD. Of PACD patients, 72.1% were female with the sex ratio (F/M) of 2.6, and the average age of patients was 63.8±9.3 years with the majority between 60 and 70 years. Additionally, 30% of these patients had low vision in one eye, 8.8% had low vision in both eyes, 1.7% had blindness in one eye, and 0.3% had blindness in both eyes. There were statistical differences with regards to age between male and female patients with PACD, with male patients being older on average. Primary angle-closure glaucoma was more commonly diagnosed in males (60%) compared to females (35.9%), whereas acute primary angle closure (APAC) was more commonly diagnosed in females (54.3%) compared to males (37.7%). The visual acuity in APAC patients was lower and the rate of low vision and blindness was higher than other subtypes.

Conclusion: PACD was the major type of glaucoma in Chinese hospitals. There were more female patients with PACD, mostly between 60 and 70 years old, with higher rates of APAC in women. APAC resulted in the worst visual outcomes of all PACD subtypes.
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http://dx.doi.org/10.1016/j.jcjo.2020.12.010DOI Listing
January 2021

Effect of Tidal Volume on Pulmonary Outcomes After Surgery.

JAMA 2021 01;325(3):306

Department of Pain Management, Beijing Tiantan Hospital, Beijing, China.

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http://dx.doi.org/10.1001/jama.2020.22627DOI Listing
January 2021

The Efficacy and Safety of the Application of Pulsed Radiofrequency, Combined With Low-Temperature Continuous Radiofrequency, to the Gasserian Ganglion for the Treatment of Primary Trigeminal Neuralgia: Study Protocol for a Prospective, Open-Label, Parall.

Pain Physician 2021 01;24(1):89-97

Department of Anesthesiology and Pain Management, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Background: Trigeminal neuralgia is a very painful condition, and radiofrequency therapy is reserved for patients who are resistant or intolerant to pharmacologic therapy. Continuous radiofrequency (CRF) and pulsed radiofrequency (PRF) both have advantages and disadvantages. Recently, studies have found that PRF combined with low-temperature (< 65°C) CRF increases the efficacy of treatment, without leading to a significant increase in complications caused by nerve lesions. However, these reports have some limitations.

Objectives: We plan to conduct a randomized, controlled study to compare the efficacy of applying high-voltage PRF, with and without low-temperature CRF, to the Gasserian ganglion for the treatment of trigeminal neuralgia.

Study Design: A study protocol for a prospective, open-label, parallel, randomized controlled trial (clinicaltrials.gov; NCT04174443).

Setting: The Department of Pain Management, Beijing Tiantan Hospital, Capital Medical University in Beijing, China.

Methods: One hundred forty-six patients with primary trigeminal neuralgia will be randomly assigned to 1 of 2 groups using an allocation ratio of 1:1. In the high-voltage PRF combined with low-temperature CRF group, 2 Hz of PRF will be applied under the following conditions: a voltage of 70 V, temperature of 42°C, pulse width of 20 ms, and treatment time of 600 s. Low-temperature CRF will then be performed at 60°C, with a treatment time of 270 s. In the high-voltage PRF group, only high-voltage PRF will be performed, using the same treatment parameters. Follow-up process will last for a duration of 1 year.

Results: The primary outcome will be the effectiveness of the treatment after 12 months, which is the percentage of patients with a modified Barrow Neurological Institute Pain Intensity Score (BNI) between I and III. The secondary outcome will include the following: BNI score, Numeric Rating Scale, dose of carbamazepine or oxcarbazepine, patient satisfaction score, quality of life, numbness, side effects, and adverse reactions. These will be recorded over a 1-year follow-up period.

Limitations: The open-label study design may influence the measurement of outcomes and introduce bias, for example, performance or ascertainment bias.

Conclusions: To our knowledge, this will be the first prospective, open-label, parallel, randomized controlled trial to compare the efficacy and safety of the application of high-voltage PRF, combined with and without low-temperature (60°C) CRF, for the patients who have failed to respond to pharmacologic treatments for primary trigeminal neuralgia. If proven effective, this will be an important, safe, minimally destructive alternative treatment modality for primary trigeminal neuralgia following an ineffective conservative treatment.
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January 2021

Effect of duloxetine premedication for postherpetic neuralgia within 72 h of herpes zoster reactivation [PROCESS]: a study protocol for a randomized controlled trial.

Trials 2020 Dec 9;21(1):1012. Epub 2020 Dec 9.

Department of Pain Management, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Background: Postherpetic neuralgia (PHN) is the most common complication attributed to herpes zoster, which involves the reactivation of residual varicella zoster virus. It has been reported previously that pre-emptive amitriptyline following acute herpes zoster has shown latent positive effects in the prevention of PHN. In this study, by interfering with the same targets, norepinephrine and serotonin, we aim to evaluate whether pre-emptive duloxetine may proactively prevent PHN development.

Methods: This is a nationwide multicentric, randomized, open-label, blinded-endpoint study that will recruit 750 participants from 18 primary centres in China. Patients aged more than 50 years who are diagnosed with uncomplicated HZ, present with vesicles within 72 h of their emergence, and have an average pain score of at least 40/100 mm on a visual analogue scale (VAS, 0 mm = no pain, 100 mm = worst possible pain, at opposite ends of a 100-mm line) will be recruited for this study. Participants will be randomized into a duloxetine arm and a control arm. Participants allocated to the duloxetine arm will be given antivirals, analgesics and duloxetine, while those allocated to the control arm will receive antivirals and analgesics but no duloxetine. The primary outcome of this study is preventive efficacy against PHN, which will be evaluated based on a 100 mm VAS. Any pain scores other than 0 mm on the VAS 12 weeks after HZ onset will be defined as PHN. The secondary outcomes will consist of the average weekly VAS score, the average weekly consumption of each analgesic, weekly feature of the pain, patients' quality of life based on the 12-item Short-Form Health Survey, Patient Global Impression of Change Scale, sleep quality as evaluated by the Pittsburgh Sleep Quality Index and adverse events during the study period.

Discussion: This study will investigate a prophylactic approach for reducing the prevalence of postherpetic neuralgia with duloxetine and will add significant new knowledge on the preventive effects of duloxetine on PHN.

Trial Registration: Clinicaltrials.gov NCT04313335 . Registered on 18 March 2020.
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http://dx.doi.org/10.1186/s13063-020-04919-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724804PMC
December 2020

Upregulation of FoxO3a expression through PI3K/Akt pathway attenuates the progression of lupus nephritis in MRL/lpr mice.

Int Immunopharmacol 2020 Dec 8;89(Pt A):107027. Epub 2020 Oct 8.

Department of Rheumatology, Shenzhen Hospital, Southern Medical University, The Third School of Clinical Medicine, Southern Medical University, China.

FoxO3a plays key roles in inflammation and autoimmunity, and the PI3K-Akt-FoxO3a pathway has been proposed to modulate diverse biological processes. The aim of the present study, using lupus murine models, was to investigate whether FoxO3a contributes to the pathogenesis of lupus nephritis. LY294002 was used as an inhibitor of PI3K/AKT signaling pathway. FoxO3a-targeted small interfering RNA (siRNA) was also used for in vivo intervention. Female MRL/lpr mice were separately injected with LY294002, LY294002+siFoxO3a, and LY294002+siControl for 8 weeks. C57BL/6 mice were normal controls. Disease development, including serum creatinine (CRE), blood urea nitrogen (BUN), proteinuria, and renal pathological changes, was monitored. Levels of anti-dsDNA antibodies and immune complex (IC) deposition in the kidney were also measured. The expression of proteins was evaluated. We found that significant downregulation of FoxO3a was detected in the kidney of MRL/lpr mice as compared with normal control mice. Blockade of p-FoxO3a activation by LY294002 suppressed PI3K/Akt/FoxO3a pathway and the subsequent upregulation of FoxO3a in the nucleus resulting in the severity of inflammation and fibrosis in the kidney of MRL/lpr mice. Also, improved kidney function and decreased circulating anti-dsDNA antibodies were due to the upregulation of FoxO3a. Opposite results were obtained by specific siRNA silencing of Foxo3a in vivo. In conclusion, our research demonstrated that the upregulation of FoxO3a expression through inhibiting PI3K/Akt pathway attenuates murine lupus nephritis (LN). Thus, our results suggest that targeting of FoxO3a can be considered as a novel strategy for the treatment of LN.
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http://dx.doi.org/10.1016/j.intimp.2020.107027DOI Listing
December 2020

Genome-wide identification and characterization of nonspecific lipid transfer protein (nsLTP) genes in Arachis duranensis.

Genomics 2020 11 24;112(6):4332-4341. Epub 2020 Jul 24.

College of Agronomy, Qingdao Agricultural University, Dry-land Farming Technology Laboratory of Shandong Province, Peanut Industry Collaborative Innovation Center of Shandong Province, Key Laboratory of Qingdao Major Crop Germplasm Resource Innovation and Application, Qingdao 266109, China. Electronic address:

Nonspecific lipid transfer proteins (nsLTPs) play vital roles in lipid metabolism, cell apoptosis and biotic and abiotic stresses in plants. However, the distribution of nsLTPs in Arachis duranensis has not been fully characterized. In this study, we identified 64 nsLTP genes in A. duranensis (designated AdLTPs), which were classified into six subfamilies and randomly distributed along nine chromosomes. Tandem and segmental duplication events were detected in the evolution of AdLTPs. The K and ω values differed significantly between Types 1 and D subfamilies, and eight AdLTPs were under positive selection. The expression levels of AdLTPs were changed after salinity, PEG, low-temperature and ABA treatments. Three AdLTPs were associated with resistance to nematode infection, and DOF and WRI1 transcription factors may regulate the AdLTP response to nematode infection. Our results may provide valuable genomic information for the breeding of peanut cultivars that are resistant to biotic and abiotic stresses.
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http://dx.doi.org/10.1016/j.ygeno.2020.07.034DOI Listing
November 2020

Predictors of the Analgesic Efficacy of CT-Guided Percutaneous Pulsed Radiofrequency Treatment of Gasserian Ganglion in Patients With Idiopathic Trigeminal Neuralgia.

Pain Pract 2020 11 30;20(8):850-858. Epub 2020 Jun 30.

Department of Pain Management, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Aims: Although pulsed radiofrequency (PRF) has few postoperative adverse reactions, its analgesic efficacy for trigeminal neuralgia (TN) is not always guaranteed. The response rate of PRF targeting the Gasserian ganglion for patients with TN varies. This study aims to identify the predictors of the analgesic efficacy of CT-guided percutaneous PRF in patients with idiopathic TN.

Methods: The patients with idiopathic TN who failed to respond to conservative treatment and underwent CT-guided percutaneous PRF treatment of the Gasserian ganglion from July 2008 to August 2018 at our pain clinic were screened. A positive response was defined as a ≥50% reduction in the pain numeric rating scale (NRS) score from baseline. The demographics and other pretreatment clinical data were analyzed by logistic regression analysis to identify the predictors of a positive response.

Results: Of the total 102 patients with idiopathic TN who were evaluated in this study, 57 patients (55.9%) were positively responsive to our treatment after 1 year. The binary logistic regression analysis revealed that the positive response to a prior peripheral branch nerve block of the trigeminal nerve with steroid and local anesthetic agents was an independent predictor of the analgesic efficacy of PRF treatment (odds ratio [OR] = 3.685, 95% confidence interval [CI] = 1.583 to 8.577, P = 0.002). The disease duration of TN was also included in the multivariate regression model, although the P value was 0.058 (OR 0.807, 95% CI 0.646 to 1.007).

Conclusion: For patients who previously had positive responses to peripheral branch nerve block of the trigeminal nerve, PRF is likely to have better efficacy.
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http://dx.doi.org/10.1111/papr.12910DOI Listing
November 2020

A Preclinical Investigation into the Effects of Aging on Dermal Hyaluronan Properties and Reconstitution Following Recombinant Human Hyaluronidase PH20 Administration.

Dermatol Ther (Heidelb) 2020 Jun 2;10(3):503-513. Epub 2020 May 2.

Halozyme Therapeutics, Inc., San Diego, CA, 92121, USA.

Introduction: There is currently no consensus in the literature concerning the impact of aging on the properties of hyaluronan (HA) in the subcutaneous (SC) space. Recombinant human hyaluronidase PH20 (rHuPH20) facilitates SC administration of injected therapeutics by depolymerizing SC HA, facilitating bulk fluid flow, dispersion and absorption. This study assessed the impact of intrinsic aging on HA in the SC space and thus the ability of rHuPH20 to enhance delivery of co-administered therapeutics.

Methods: Histologic evaluations of HA levels and degradation were performed on human skin samples from six age groups, aged from 20 to 100 years. HA levels were evaluated by HA staining and degradation by staining samples for HA following incubation with rHuPH20. HA was extracted from samples and HA size determined by gel electrophoresis. Dermal reconstitution was assessed in young (aged 1.5 months) and elderly (aged > 16 months) mice. Baseline dye dispersion was measured at 5 and 20 min post-intradermal dye injection. Following treatment with rHuPH20, dye dispersion was measured again at 2, 24, 48, 72 and 96 h.

Results: Distribution of HA was confined to the interstitial space between adipocytes, with similar pericellular presence and levels of HA found across all age groups. Substantial levels of high-molecular-weight HA were observed in all age groups at baseline. Incubation with a clinically relevant dose of rHuPH20 resulted in degradation of all SC HA and similar degradation profiles independent of age. No difference in dye dispersion time was observed between young and elderly mice across the range of time points assessed, with dye dispersion returning to baseline levels by 24 h after rHuPH20 treatment.

Conclusions: Subcutaneous delivery of approved therapeutics facilitated by co-administration with rHuPH20 should not be impacted by intrinsic aging, with this study providing no evidence for an effect of aging on HA distribution, structure or a loss of rHuPH20 efficacy.
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http://dx.doi.org/10.1007/s13555-020-00380-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211778PMC
June 2020

Anti-liver fibrosis effect of total flavonoids from Scabiosa comosa Fisch. ex Roem. et Schult. on liver fibrosis in rat models and its proteomics analysis.

Ann Palliat Med 2020 Mar 18;9(2):272-285. Epub 2020 Mar 18.

Department of Pharmacology, Inner Mongolia Medical University, Hohhot City 010107, China.

Background: To explore the potential therapeutic effect of total flavonoids (TFs) extracted from Scabiosa comosa Fisch. ex Roem. et Schult on liver fibrosis in rat models and to identify the possible targets and pathways of TF in treating liver fibrosis by using a quantitative proteomics method.

Methods: Sixty Wistar rats were equally randomized into five groups: a blank control group, a model group, and high-, intermediate-, and low-dose TF treatment groups. Except for the blank control group, rats in the other four groups were intragastrically administered with CCL4 2 mL/kg to establish the liver fibrosis models. Furthermore, the high-, intermediate-, and low-dose TF groups were intragastrically given TF at a dose of 200, 100 and 50 mg/kg, respectively. After 10 weeks, the rats were sacrificed, and blood and liver samples were collected. Serum alanine transaminase (ALT), Aspartate aminotransferase (AST), and alkaline phosphatase (ALP) levels were measured, and hematoxylin and eosin (HE) staining and Masson's trichrome staining were used to observe the pathological changes in each group. The hydroxyproline content was also determined. Real-time polymerase chain reaction (PCR) and Western blotting (WB) were performed to detect the mRNA and protein expressions of α-smooth muscle actin (αSMA) and Collagen I. Mass spectrometry was performed for proteomic analysis.

Results: Compared with the blank control group, the model group had significantly higher ALT, AST, ALP, and hydroxyproline levels; also, HE and Masson staining showed fibrotic lesions and inflammatory cell infiltration in the model group. Compared with the model group, the high-, intermediate-, and lowdose TF groups had significantly decreased ALT, AST, and ALP levels (P<0.05), and a significantly lower hydroxyproline level (P<0.05), along with remarkably improved fibrotic lesions and inflammatory cell infiltration. Real-time PCR and WB showed that the model group had significantly higher expressions of αSMA and collagen I than those in the blank control group, whereas the TF groups had significantly lower expressions of αSMA and collagen I than those in the model group. A total of 5,014 proteins were detected by quantitative proteomics, among which 205 proteins were differentially expressed, 77 of which were upregulated and 128 of which were down-regulated. KEGG pathway analysis indicated that the peroxisome proliferator activated receptor (PPAR) and ECM-receptor interaction pathways were down-regulated in the TF groups compared with the model group. Among them, fatty-acid-binding protein (FABP) and von Willebrand factor (vWF) were the key proteins in the PPAR and extracellular matrix (ECM)-receptor interaction pathways. The proteomic results were validated by using WB, yielding consistent results.

Conclusions: Our result demonstrated that the TF extract of Scabiosa comosa Fisch. ex Roem. et Schult has a good anti-liver fibrosis effect and may prevent liver fibrosis by reducing the content of α-SMA, CollagenⅠ in liver tissue. The anti-fibrosis mechanism of TF extract of Scabiosa comosa Fisch. ex Roem. et Schult may be the inhibition of key proteins FABP and vWF in PPAR, ECM RECEPTOR INTERACTION pathway.
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http://dx.doi.org/10.21037/apm.2020.02.29DOI Listing
March 2020

Decreased expression of IGFBP6 correlates with poor survival in colorectal cancer patients.

Pathol Res Pract 2020 May 29;216(5):152909. Epub 2020 Feb 29.

Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China; Clinical Tissue Bank, Department of Pathology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China. Electronic address:

Background: The insulin-like growth factor binding protein 6 (IGFBP6), as a specific inhibitor of IGF-Ⅱ, is a candidate human anti-oncogene in multiple tumors. However, the expression of IGFBP6 in colorectal cancer (CRC) and prognostic significance are unclear.

Methods: In this study, we examined colorectal cancer tissues and adjacent normal tissues to determine the expression levels of IGFBP6 mRNA and protein by quantitative reverse-transcription polymerase chain reaction and tissue microarray immunohistochemistry analysis respectively. Moreover, we explored the effects of IGFBP6 on cell growth, migration and invasion by Cell Counting Kit-8(CCK8), colony formation and transwell migration assays. We also investigated whether IGFBP6 expression in tumor tissue correlated with various clinical parameters, including overall survival by univariate and multivariate analyses RESULTS: Both IGFBP6 mRNA and protein levels were significantly lower in colorectal cancer tissues than in adjacent normal colon. Downregulating IGFBP6 using RNAi increased CRC cell proliferation, migration and invasion. Low IGFBP6 expression correlated with poor overall survival in both univariate and multivariate analyses.

Conclusion: Our data suggest that IGFBP6 may act as a tumor suppressor gene in the development of CRC, and that low IGFBP6 expression could be used as an independent prognostic biomarker in CRC.
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http://dx.doi.org/10.1016/j.prp.2020.152909DOI Listing
May 2020

Do toxicokinetic and toxicodynamic processes hold the same for light and heavy rare earth elements in terrestrial organism Enchytraeus crypticus?

Environ Pollut 2020 Jul 20;262:114234. Epub 2020 Feb 20.

School of Environmental Science and Engineering, Sun Yat-sen University, Guangzhou, 510006, China; Guangdong Provincial Key Lab for Environmental Pollution Control and Remediation Technology, Sun Yat-sen University, Guangzhou, 510006, China; Guangdong Laboratory for Lingnan Modern Agriculture, South China Agriculture University, Guangzhou, 510642, China.

The widespread use of rare earth elements (REEs) in numerous sectors have resulted in their release into the environment. Existing knowledge about the effects of REEs were acquired mainly based on toxicity tests with aquatic organisms and a fixed exposure time, Here, the dynamic accumulation and toxicity of REEs (La, Ce, and Gd) in soil organism Enchytraeus crypticus were determined and modeled by a first-order one-compartment model and a time-toxicity logistic model, respectively. Generally, the accumulation and toxicity of REEs were both exposure level- and time-dependent. The overall uptake rate constants were 2.97, 2.48, and 2.38 L kgd for La, Ce, and Gd, respectively. The corresponding elimination rate constants were 0.99, 0.78, and 0.56 d, respectively. The worms exhibited faster uptake and elimination ability for light REEs (La and Ce) than for heavy REEs (Gd). For all three REEs, the LC50 values based on exposure concentrations decreased with time and reached ultimate values after approximately 10 d exposure. The estimated ultimate LC50 values (LC50∞) were 279, 334, and 358 mg L for Ce, Gd, and La, respectively. When expressed as body concentration, the LC50 value was almost constant with time, demonstrating that internal body concentration could be a better indicator of dynamic toxicity of REEs than external dose. This study highlights that specific REE and exposure time should be taken into account in accurately assessing risk of REEs.
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http://dx.doi.org/10.1016/j.envpol.2020.114234DOI Listing
July 2020

The growth of a xenograft breast cancer tumor model with engineered hyaluronan-accumulating stroma is dependent on hyaluronan and independent of CD44.

Oncotarget 2019 Nov 12;10(61):6561-6576. Epub 2019 Nov 12.

Halozyme Therapeutics, Inc., San Diego, CA, 92121, USA.

Hyaluronan accumulation in the tumor microenvironment is associated with poor prognosis in several solid human cancers. To understand the role of stromal hyaluronan in tumor progression, we engineered 3T3HAS3, a hyaluronan-producing fibroblast cell line, by lentiviral transduction of Balb/c 3T3 cells with the gene. 3T3HAS3 cells significantly enhanced tumor growth when co-grafted with MDA-MB-468 cells in nude mice. Immunohistochemical analysis of the xenograft tumors showed that MDA-MB-468 cells were surrounded by hyaluronan-accumulating stroma, closely resembling the morphology observed in human breast cancer specimens. Tumor growth of MDA-MB-468 + 3T3HAS3 co-grafts was greatly reduced upon hyaluronan degradation by lentiviral transduction of a human hyaluronidase gene in 3T3HAS3 cells, or by systemic administration of pegvorhyaluronidase alfa (PEGPH20). In contrast, the growth of the co-graft tumors was not inhibited when CD44 expression was reduced or ablated by small hairpin RNA-mediated CD44 knockdown in MDA-MB-468 cells, CD44 CRISPR knockout in 3T3HAS3 cells, or by grafting these cells in CD44 knockout nude mice. Collectively, these data demonstrate that tumor growth of an engineered xenograft breast cancer model with hyaluronan-accumulating stroma can be dependent on hyaluronan and independent of CD44.
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http://dx.doi.org/10.18632/oncotarget.27302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859925PMC
November 2019

Associations of ambient temperature exposure during pregnancy with the risk of miscarriage and the modification effects of greenness in Guangdong, China.

Sci Total Environ 2020 Feb 2;702:134988. Epub 2019 Nov 2.

Guangdong Provincial Institute of Public Health, Guangdong Provincial Center for Disease Control and Prevention, Guangzhou 511430, China; General Practice Center, Nanhai Hospital, Southern Medical University, Foshan 528200, China. Electronic address:

Miscarriage is one of the commonest complications of pregnancy. Although previous studies suggested that environmental factors were important causes of miscarriage, evidence is still inadequate. Here, we examined the association of maternal exposure to temperature with the risk of miscarriage and further assessed the modifying effects of surrounding residential greenness. A case-control study was conducted at a large hospital in Guangzhou, China. All participants' information was extracted from hospital records. An inverse distance weighted method was used to estimate the temperature exposure at each residential address, where the greenness was measured by Normalized Difference Vegetation Index (NDVI). A logistic regression model was applied to estimate the association of temperature exposure with the risk of miscarriage. A total of 2044 cases of miscarriage and 2285 controls were included in the present study. We observed a generally non-linear positive relationship between temperature exposure and the risk of miscarriage. More pronounced effects of high temperatures vs. low temperatures were found during the two months prior to hospitalization than in other periods. The odds ratio (OR) of 29.4 °C (95th centile) compared with 15 °C during the first month prior to hospitalization was 1.480 (95% CI: 1.021-2.145). Smaller effects of temperatures were seen on the risk of miscarriage among participants with moderately great surrounding greenness compared with those with less greenness. We concluded that maternal exposure to moderately high temperature during pregnancy may increase the risk of miscarriage, but the modifying effects of greenness on these associations need to be further tested in future studies.
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http://dx.doi.org/10.1016/j.scitotenv.2019.134988DOI Listing
February 2020

Long-term Outcomes of Computerized Tomography-Guided Sphenopalatine Ganglion-Targeted Pulsed Radiofrequency for Refractory Cluster Headache.

Pain Pract 2020 03 21;20(3):289-296. Epub 2019 Nov 21.

Department of Pain Management, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Objective: To further evaluate the efficacy and safety of computerized tomography-guided sphenopalatine ganglion-targeted pulsed radiofrequency treatment for patients with refractory episodic and chronic cluster headache (CH).

Methods: Forty-five patients with refractory episodic CH and 14 patients with chronic CH who underwent computerized tomography-guided sphenopalatine ganglion-targeted pulsed radiofrequency between January 2011 and December 2018 at the Beijing Tiantan Hospital were included and analyzed in this retrospective cohort study.

Results: A total of 59 patients underwent 106 computerized tomography-guided pulsed radiofrequency procedures throughout the observational period. Effective remission was observed in 95.6% and 64.3% of patients with refractory episodic and chronic CH, respectively. Repeated computerized tomography-guided sphenopalatine ganglion-targeted pulsed radiofrequency procedures for recurrent CH was also proven to be effective. No severe side effects or complications were observed in this study.

Conclusion: The computerized tomography-guided sphenopalatine ganglion-targeted pulsed radiofrequency procedure is an effective, safe, and repeatedly effective strategy for refractory CH. For patients who have not responded to conservative treatment, this minimally invasive intervention is a reliable alternative.
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http://dx.doi.org/10.1111/papr.12853DOI Listing
March 2020

The responses of a soil bacterial community under saline stress are associated with Cd availability in long-term wastewater-irrigated field soil.

Chemosphere 2019 Dec 15;236:124372. Epub 2019 Jul 15.

Guangdong Provincial Key Laboratory of Environmental Pollution Control and Remediation Technology, Sun Yat-sen University, Guangzhou, 510275, PR China.

Long-term wastewater irrigation impacts soil geochemical properties (salinity, pH and soil aggregates) and promotes the bioaccumulation of heavy metals to plants, which may change soil function, decrease soil health, decrease the productivity of farmland, and even cause land degradation. In this study, we explored the impact of saline stress on soil bacterial communities and Cd availability in long-term wastewater-irrigated field soil. Different amounts of saline stress by adding 0.1, 0.3 and 0.5% salts in a fixed proportion (NaCl: NaSO: NaHCO: NaCO = 1:9:9:1) were applied in a 1-year, multiple cropping system with winter wheat (Triticum aestivum L.) and summer maize (Zea mays L.) in wastewater-polluted soil. Increased salinity in the soil increased Cd availability: compared with CK (no extra salts addition), addition of 0.5% mixed salts significantly increased soil available Cd up by 67.5% and grain Cd concentration by 43.7%, and adding 0.5% salts also resulted in the increases of soil pH (∼0.5 unit) and electric conductivity (97.4%). Soil saline stress significantly changed major soil microbes in Cd-contaminated soil. Increased saline stress enriched taxa in the Bacillaceae, Staphylococcaceae and Pseudomonadaceae bacterial families, while one family within Proteobacteria (Sphingomonadaceae) was the most sensitive biomarker, based on Cd contamination without saline stress in CK-treated soils. Structural equation modeling (SEM) analysis revealed that soil saline stress induced an increase in soil Cd availability that was regulated by the bacterial community.
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http://dx.doi.org/10.1016/j.chemosphere.2019.124372DOI Listing
December 2019

Pre-emptive scalp infiltration with ropivacaine plus methylprednisolone versus ropivacaine alone for relief of postoperative pain after craniotomy in children (RP/MP vs RP): a study protocol for a randomised controlled trial.

BMJ Open 2019 06 22;9(6):e027864. Epub 2019 Jun 22.

Department of Pain Management, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Introduction: Pre-emptive scalp infiltration with local anaesthetics is the simplest and most effective method to prevent postoperative incisional pain. However, local infiltration of an anaesthetic only provides relatively short-term pain relief. Methylprednisolone (MP) treatment, administered as an adjuvant at the wound site, has been shown to provide satisfactory pain management after lumbar laminectomy. However, there is no evidence regarding the efficacy of MP infiltration for the relief of postoperative pain after craniotomy. Currently, postoperative pain after craniotomy in children is undertreated. Therefore, we aim to investigate whether pre-emptive scalp infiltration with ropivacaine (RP) plus MP is superior to RP alone to improve postoperative pain after craniotomy in children.

Methods And Analysis: The RP/MP versus RP trial is a prospective, single-centre, randomised, parallel-group study of 100 children aged 8-18 years undergoing intracranial surgery. Participants will be randomly allocated to receive pre-emptive scalp infiltration with either RP plus MP or RP alone. The primary outcome will be the cumulative fentanyl dose administered by patient-controlled intravenous analgesia within 24 hours postoperatively. The secondary outcomes will include postoperative Numerical Rating Scale scores, pain control satisfaction scores, length of stay and adverse events. Data will be analysed by the intention-to-treat principle.

Ethical Approval And Dissemination: The study protocol has been approved by the Institutional Review Board of Beijing Tiantan Hospital Affiliated to Capital Medical University (Approval Number: KY 2018-066-02). The results will be disseminated in international academic meetings and published in peer-reviewed journals.

Trial Registration Number: NCT03636165; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2018-027864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596953PMC
June 2019

Pre-emptive scalp infiltration with dexamethasone plus ropivacaine for postoperative pain after craniotomy: a protocol for a prospective, randomized controlled trial.

J Pain Res 2019 24;12:1709-1719. Epub 2019 May 24.

Department of Pain Management, Beijing Tiantan Hospital, Capital Medical University, Beijing, People's Republic of China.

Approximately 55-87% of the patients undergoing craniotomy experience moderate to severe pain during the first 48 hrs after surgery, which negatively influences patients' postoperative rehabilitation. Recently, local infiltration of analgesia (LIA) has been widely performed clinically as a promising analgesic method that could avoid the side effects of analgesics but only has a short pain-free duration; researchers have clarified that the addition of dexamethasone to LIA could provide significant analgesic effects and significantly prolong the duration of analgesic effects without obvious complications for various types of surgeries. To date, no studies have evaluated the addition of dexamethasone to LIA for patients receiving craniotomy. The aim of the study was to test the hypothesis that pre-emptive scalp infiltration with a steroid (dexamethasone) plus a local anesthetic (ropivacaine) could achieve superior postoperative analgesic effects to a local anesthetic (ropivacaine) alone in adult patients undergoing a craniotomy. This study is a randomized controlled trial that will include one intervention and one control group involving a total of 140 adults scheduled for elective craniotomy for resection of supratentorial tumors under general anesthesia and with an anticipated full recovery within 2 hrs postoperatively. The intervention will involve pre-emptive scalp infiltration with ropivacaine plus dexamethasone (the dexamethasone group) or ropivacaine alone (the control group), and the participants in both groups will complete a 6-month follow-up. The primary outcome will be the cumulative sufentanil consumption within 48 hrs postoperatively. The intervention, if effective, this study will provide clinically important information on the role of dexamethasone in scalp infiltration for post-craniotomy pain management.
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http://dx.doi.org/10.2147/JPR.S190679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542215PMC
May 2019

High Expression of LTBP2 Contributes to Poor Prognosis in Colorectal Cancer Patients and Correlates with the Mesenchymal Colorectal Cancer Subtype.

Dis Markers 2019 10;2019:5231269. Epub 2019 Mar 10.

Department of Laboratory Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001 JS, China.

Colorectal cancer (CRC) is a complex and heterogeneous disease with four consensus molecular subtypes (CMS1-4). LTBP2 is a member of the fibrillin/LTBP super family and plays a critical role in tumorigenesis by activating TGF- in the CMS4 CRC subtype. So far, the expression and prognostic significance of LTBP2 in CRC remains obscure. In this study, we aimed to analyze the mRNA and protein expression levels of LTBP2 in CRC tissues and then estimate their values as a potential prognostic biomarker. We detected the mRNA expression of LTBP2 in 28 cases of fresh CRC tissues and 4 CRC cell lines and the protein expression of LTBP2 in 483 samples of CRC tissues, matched tumor-adjacent tissues, and benign colorectal diseases. LTBP2 protein expression was then correlated to patients' clinical features and overall survival. Both LTBP2 mRNA and protein expression levels in CRC tissues were remarkably superior to those in adjacent normal colorectal tissues ( = 0.0071 and < 0.001, respectively), according to TCGA dataset of CRC. High LTBP2 protein expression was correlated with TNM stage ( < 0.001), T stage ( < 0.001), N stage ( < 0.001), and M stage ( < 0.001). High LTBP2 protein expression was related to poor overall survival in CRC patients and was an independent prognostic factor for CRC. LTBP2 mRNA expression was especially higher in the CMS4 subtype ( < 0.001), which was confirmed in CRC cell lines. Our data suggested that LTBP2 may act as an oncogene in the development of colorectal cancer and have important significance in predicting CRC prognosis. LTBP2 could be a novel biomarker and potential therapeutic target for mesenchymal colorectal cancer and can improve the outcome of high-risk CRC.
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http://dx.doi.org/10.1155/2019/5231269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431450PMC
August 2019

KRAS-mutant colon cancer cells respond to combined treatment of ABT263 and axitinib.

Biosci Rep 2019 03 6;39(3). Epub 2019 Mar 6.

Department of Laboratory Medicine Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong 226001, JS, People's Republic of China

Significant challenges to develop selective and effective pharmacological inhibitors for important oncoproteins like RAS continue impeding the success to treat cancers driven by such mutations. In the present study, the ABT263 and axitinib combination imposed synergistic effects on -mutant colon cancer cells. The combination inhibited and growth of the cancer cells by enhancing apoptosis. Furthermore, AKT and Wnt/β-catenin signaling pathways were slightly down-regulated by the combination in -mutant colon cancer cells. The current results indicate that oncogene addiction can be targeted for therapy in colon cancer cells harboring the -mutant. Therefore, targeting oncogene addiction can be a viable strategy for treating refractory cancers driven by important oncogenes, such as , which are otherwise difficult to be targeted by small molecules.
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http://dx.doi.org/10.1042/BSR20181786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400663PMC
March 2019

NLRP3 inflammasome regulates Th17 differentiation in rheumatoid arthritis.

Clin Immunol 2018 12 17;197:154-160. Epub 2018 Sep 17.

Department of Radiology, Shenzhen Hospital, Southern Medical University, 1333 Xinhu Road, Shenzhen 518100, China.

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases. Th17 has been shown to play am important role in the pathogenesis of RA. Accumulating data suggest the involvement of NLRP3 inflammasome in Th17 differentiation in autoimmune diseases. In the current study, we found that NLRP3 inflammasome is activated in CD4 T cells from RA patients. The activation of NLRP3 inflammasome was correlated with disease activities and IL-17A concentration in RA sera. Knockdown of NLRP3 suppressed Th17 differentiation. In addition, caspase-1 or IL-1 receptor inhibitor inhibits Th17 differentiation significantly. Further, ROS production is increased in CD4 T cells from RA patients. The inhibition of ROS production decreased NLRP3 inflammasome activation and IL-1β production in CD4 T cells, leading to the suppression of Th17 differentiation. These findings suggest a pathogenic role of NLRP3 inflammasome in RA by promoting Th17 cell differentiation. NLRP3 inflammasome could be a potential therapeutic target for the treatment of RA.
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http://dx.doi.org/10.1016/j.clim.2018.09.007DOI Listing
December 2018

Identification specific miRNA in t(4;14) multiple myeloma based on miRNA-mRNA expressing profile correlation analysis.

J Cell Biochem 2018 Sep 19. Epub 2018 Sep 19.

Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.

Background: Multiple myeloma (MM) is a common malignancy belonging to the hematological system. The translocation t(4;14)(p16.3;q32.3) is a critical cytogenetic change of MM, which is presenting a poor prognosis. The specific microRNAs (miRNAs) that are involved in t(4;14) myeloma are still unknown. Thus, the main purpose of this research was to identify specific miRNAs in t(4;14) positive myeloma.

Methods: The expression profiles of miRNA and messenger RNA (mRNA) in t(4; 14) positive and negative samples were obtained from the gene expression omnibus data series. The miRNA-mRNA regulatory network was constructed based on two self-defined regulation models. Subsequently, we performed the topology analysis for mining the hub genes, and Pearson's correlation coefficient analysis was used to calculate the relevance of the hub genes and specific miRNAs.

Results: Thirteen differentially expressed miRNAs and 206 differential mRNAs were extracted between t(4;14) positive group and negative group. The network consisted of 8 miRNAs and 154 mRNAs in 2 reverse regulated models, which showed a total of 485 interactions, including 376 cis-regulated and 109 trans-regulated relationships. The miR-125a-3p, miR-125a-5p, miR-99b-5p, and let-7e were powerful miRNAs correlating with the FGFR3, MAP1B, MYRIP, and CDC42BPA under the relevance analysis in the subnetwork.

Conclusion: In our study, a distinctive correlation analysis of miRNA-mRNA was established to excavate specific miRNAs and hub target mRNAs in patients with t(4;14), but it was only a matter of theoretical principles. The further experimental explorations are needed to confirm valuable diagnostic and therapeutic symbols specific associated with t(4;14) in the future.
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http://dx.doi.org/10.1002/jcb.27537DOI Listing
September 2018

Manipulation of the rhizosphere bacterial community by biofertilizers is associated with mitigation of cadmium phytotoxicity.

Sci Total Environ 2019 Feb 16;649:413-421. Epub 2018 Aug 16.

College of Energy, Xiamen University, Xiamen, Fujian 361102, PR China.

The objective of this study was to understand the effect of biofertilizers on cadmium (Cd)-induced phytotoxicity and the rhizosphere bacterial community. The crop specie rice (Oryza sativa L.) was planted in Cd-contaminated soils, and Illumina high-throughput sequencing was performed to investigate how the composition of the rhizosphere bacterial community responded to the addition of biofertilizers. Biofertilizers were effective in alleviating Cd phytotoxicity as indicated by the significant increase in plant biomass (up to 85.2% and 48.4% for roots and shoots, respectively) and decrease in tissue Cd concentration (up to 72.2% in roots) of rice receiving fertilizer treatments compared with the CK (no treatment). These positive effects were likely due to the increase in soil pH, which can be attributed primarily to Cd immobilization, and the promotion of beneficial taxa such as Proteobacteria, Bacteroidetes, Gemmatimonadetes, and Firmicutes. In addition, autoclaved biofertilizers tended to have similar beneficial effects and similar bacterial community alpha diversities as the original biofertilizer treatments. This suggests that the change in soil physicochemical properties by biofertilizer addition might drive the structure of rhizosphere bacterial community, and not the biofertilizer microbes themselves. In both the original and sterilized biofertilizer treatments, the effectiveness in mitigating of Cd phytotoxicity was found to be dependent on the type of biofertilizer applied. Comparatively, the biofertilizer denoted as DY was more effective in mitigating Cd phytotoxicity than others. These results demonstrate that biofertilizer addition could be a promising approach to immobilize soil Cd by manipulating the rhizosphere bacterial community, thus to facilitate plant growth.
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http://dx.doi.org/10.1016/j.scitotenv.2018.08.174DOI Listing
February 2019

Parallel Accumulation of Tumor Hyaluronan, Collagen, and Other Drivers of Tumor Progression.

Clin Cancer Res 2018 10 3;24(19):4798-4807. Epub 2018 Jul 3.

Halozyme Therapeutics, Inc., San Diego, California.

The tumor microenvironment (TME) evolves to support tumor progression. One marker of more aggressive malignancy is hyaluronan (HA) accumulation. Here, we characterize biological and physical changes associated with HA-accumulating (HA-high) tumors. We used immunohistochemistry, imaging of tumor pH, and microdialysis to characterize the TME of HA-high tumors, including tumor vascular structure, hypoxia, tumor perfusion by doxorubicin, pH, content of collagen. and smooth muscle actin (α-SMA). A novel method was developed to measure real-time tumor-associated soluble cytokines and growth factors. We also evaluated biopsies of murine and pancreatic cancer patients to investigate HA and collagen content, important contributors to drug resistance. In immunodeficient and immunocompetent mice, increasing tumor HA content is accompanied by increasing collagen content, vascular collapse, hypoxia, and increased metastatic potential, as reflected by increased α-SMA. treatment of HA-high tumors with PEGylated recombinant human hyaluronidase (PEGPH20) dramatically reversed these changes and depleted stores of VEGF-A165, suggesting that PEGPH20 may also diminish the angiogenic potential of the TME. Finally, we observed in xenografts and in pancreatic cancer patients a coordinated increase in HA and collagen tumor content. The accumulation of HA in tumors is associated with high tIP, vascular collapse, hypoxia, and drug resistance. These findings may partially explain why more aggressive malignancy is observed in the HA-high phenotype. We have shown that degradation of HA by PEGPH20 partially reverses this phenotype and leads to depletion of tumor-associated VEGF-A165. These results encourage further clinical investigation of PEGPH20. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743334PMC
October 2018

Detection of miR-22, miR-140 and Bone Morphogenetic Proteins (BMP)-2 Expression Levels in Synovial Fluid of Osteoarthritis Patients Before and After Arthroscopic Debridement.

Med Sci Monit 2018 Feb 12;24:863-868. Epub 2018 Feb 12.

Department of Osteology, Tianjin Fifth Central Hospital, Tianjin, China (mainland).

BACKGROUND Osteoarthritis (OA) is a degenerative joint disease often present on the surface and edge of the joint and beneath cartilage forming new bone. Arthroscopy had been used for the treatment of knee OA. This study aimed to measure the expression of miR-22, miR-140, and BMP-2 in patients with OA before and after arthroscopy operation. MATERIAL AND METHODS The synovial fluid of 80 patients and 60 healthy volunteers were aspirated using a syringe before OA operation and again six months post-operation in patients with OA. The total RNA was extracted and analyzed by quantitative PCR. RESULTS The level of miR-22 was elevated in the progression of OA. The expression of miR-140 level in the synovial fluid was significantly reduced in the patients with OA and was negatively correlated with OA severity compared to controls. Expression of miR-22 and miR-120 returned to normal levels post-operatively. BMP-2 expression was reduced in patients with OA, and returned to normal levels post-operatively. Bioinformatics analysis showed that miR-22 and miR-140 closely target with 3'-UTR of BMP-2 in different positions. The correlation between BMP-2 and miR-22 was negative. The correlation between BMP-2 and miR-140 was positive. CONCLUSIONS The present study identified a change in miR-22, miR-140, and BMP-2 expression in the synovial fluid of patients with OA before and after arthroscopic debridement. Results provide a novel characterization of the pathogenesis and therefore underlying therapeutic target for OA.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819307PMC
http://dx.doi.org/10.12659/msm.908110DOI Listing
February 2018

Valproic acid attenuates inflammation of optic nerve and apoptosis of retinal ganglion cells in a rat model of optic neuritis.

Biomed Pharmacother 2017 Dec 2;96:1363-1370. Epub 2017 Dec 2.

Neurology Center, The General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, People's Republic of China; Ningxia Key Laboratory of Craniocerebral Diseases, Yinchuan, Ningxia, 750004, People's Republic of China; National Engineering Research Center for Beijing Biochip Technology, Sub-Center in Ningxia, Yinchuan, Ningxia, 750004, People's Republic of China. Electronic address:

Aims: Optic neuritis (ON) is an inflammatory disease of the optic nerve, which often occurs in patients with multiple sclerosis (MS) and leads to retinal ganglion cell (RGC) death and even severe visual loss. Valproic acid (VPA) is a short-chain branched fatty acid with anti-epileptic, neuro-protective and anti-inflammatory effects. Here, we examined the effects of VPA in experimental autoimmune encephalomyelitis (EAE) rats and explored the underlying mechanisms.

Main Methods: EAE was induced by subcutaneous injection with myelin basic protein, emulsified with complete Freund's adjuvant and Mycobacterium tuberculosis H37Ra into the Lewis rats. Subsequently, animals in the VPA groups were treated orally with VPA (250 or 500 mg/kg) once a day for 13 days.

Key Findings: VPA treatment significantly attenuated inflammation and microgliosis in optic nerve in EAE-ON rats, as evidenced by the decrease in the mRNA levels of interferon (INF)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-17, and inducible nitric oxide synthase (iNOS), the suppression in nuclear factor (NF)-κB signal pathway as well as the down-regulation of CD11b expression in optic nerve. Additionally, the apoptotic RGCs were remarkably increased in the EAE retina, which was inhibited by VPA treatment. Consistent with the TUNEL staining, VPA administration also obviously suppressed the ratio of Bax: Bcl-2 and the expression of cleaved caspase-3 and PARP in optic nerve in EAE rats.

Significance: Our findings demonstrated that VPA treatment could prevent inflammation responses and RGC apoptosis in optic nerve in EAE-ON rats, suggesting that VPA may be available for optic nerve protection during ON.
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http://dx.doi.org/10.1016/j.biopha.2017.11.066DOI Listing
December 2017

PH20 is not expressed in murine CNS and oligodendrocyte precursor cells.

Ann Clin Transl Neurol 2017 Mar 23;4(3):191-211. Epub 2017 Feb 23.

Halozyme Therapeutics, Inc. San Diego California.

Objective: Expression of /PH20 and its modulation of high/low molecular weight hyaluronan substrate have been proposed to play an important role in murine oligodendrocyte precursor cell (OPC) maturation in vitro and in normal and demyelinated central nervous system (CNS). We reexamined this using highly purified PH20.

Methods: Steady-state expression of mRNA in OPCs was evaluated by quantitative polymerase chain reaction; the role of PH20 in bovine testicular hyaluronidase (BTH) inhibition of OPC differentiation was explored by comparing BTH to a purified recombinant human PH20 (rHuPH20). Contaminants in commercial BTH were identified and their impact on OPC differentiation characterized. /PH20 expression in normal and demyelinated mouse CNS tissue was investigated using deep RNA sequencing and immunohistological methods with two antibodies directed against recombinant murine PH20.

Results: BTH, but not rHuPH20, inhibited OPC differentiation in vitro. Basic fibroblast growth factor (bFGF) was identified as a significant contaminant in BTH, and bFGF immunodepletion reversed the inhibitory effects of BTH on OPC differentiation. mRNA was undetected in OPCs in vitro and in vivo; PH20 immunolabeling was undetected in normal and demyelinated CNS.

Interpretation: We were unable to detect /PH20 expression in OPCs or in normal or demyelinated CNS using the most sensitive methods currently available. Further, "BTH" effects on OPC differentiation are not due to PH20, but may be attributable to contaminating bFGF. Our data suggest that caution be exercised when using some commercially available hyaluronidases, and reports of /PH20 morphogenic activity in the CNS may be due to contaminants in reagents.
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http://dx.doi.org/10.1002/acn3.393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5338182PMC
March 2017
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