Melatonin attenuates chronic intermittent hypoxia-induced intestinal barrier dysfunction in mice.

BACKGROUND AND PURPOSE: Chronic intermittent hypoxia (CIH) triggers subclinical intestinal barrier disruption prior to systemic low-grade inflammation. Increasing evidence suggests therapeutic effects of melatonin on systemic inflammation and gut microbiota remodelling. However, whether and how melatonin alleviates CIH-induced intestinal barrier dysfunction remains unclear. EXPERIMENTAL APPROACH: C57BL/6 J mice and Caco-2 cell line were treated. We evaluated gut barrier function spectrophotometrically using fluorescein isothiocyanate (FITC)-labelled dextran. Immunohistochemical and immunofluorescent staining were used to detect morphological changes in the mechanical barrier. Western blotting (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) revealed the expression of tight junctions, signal transducer and activator of transcription 3 (STAT3) levels. 16 S rRNA analysis of the colonic contents microflora. Flow cytometry was used to detect cytokines and Th17 cells with and without melatonin supplementation. KEY RESULTS: We found that CIH could induce colonic mucosal injury, including reduction in the number of goblet cells and decrease the expression of intestinal tight junction proteins. CIH could decrease the abundance of the beneficial genera Clostridium, Akkermansia, and Bacteroides, while increasing the abundance of the pathogenic genera Desulfovibrio and Bifidobacterium. Finally, CIH facilitated Th17 differentiation via the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in vitro and elevated the circulating pro-inflammatory cytokine in vivo. Melatonin supplementation ameliorated CIH-induced intestinal mucosal injury, gut microbiota dysbiosis, enteric Th17 polarization, and systemic low-grade inflammation reactions mentioned-above. CONCLUSION AND IMPLICATIONS: Melatonin attenuated CIH-induced intestinal barrier dysfunction by regulating gut flora dysbiosis, mucosal epithelium integrity, and Th17 polarization via STAT3 signalling.

Yin-Yang tongue sign: An imaging clue of lesions involving the skull base segment in the hypoglossal pathway.

OBJECTIVE: To investigate the diagnostic value of the Yin-Yang tongue sign in patients with tongue deviation. METHODS: According to the presence of the Yin-Yang tongue sign on CT/MR, 107 patients with tongue deviation were divided into a positive group and a negative group. The involvement categories of the hypoglossal canal (HC) in the positive group were evaluated and classified as HC dilation and HC erosion. The correlations between HC involvement categories and the presence of the sign were analysed. RESULTS: There were 55 cases (55/107, 51.4%) in the positive group and 52 cases (52/107, 48.6%) in the negative group. Hypoglossal nerve (HN) involvement mainly occurred in the skull base (61.8%), skull base and carotid space (10.9%), and carotid space segment (12.7%). Neurogenic (50.9%), squamous cell carcinoma (14.5%), and metastases (12.7%) were the predominant aetiologies. The sensitivity, specificity, and accuracy of this sign for suggesting skull base lesions around HC were 72.4%, 80.8%, and 76.6%, respectively. In the positive group, HC dilation was seen in 21 patients (21/55, 38.2%) and 21 cases were all benign. HC erosion were noted in 19 patients (19/55, 34.5%), of whom 12 cases were malignant. CONCLUSION: The Yin-Yang tongue sign is formed by unilateral tongue atrophy and fat infiltration caused by lesions in the HN pathway, especially compressive or invasive lesions involving the skull base segment.

Targeted Wolfram-Doped Polypyrrole for Photonic Hyperthermia-Synergized Radiotherapy.

Single ionizing radiation at a tolerable dose is ineffectual in eliminating malignancies but readily generates harmful effects on surrounding normal tissues. Herein, we intelligently fabricated novel wolfram-doped polypyrrole (WPPy) through a simple oxidative polymerization method with WCl6 as an oxidizing catalyst, which possessed good biocompatibility, high photothermal conversion, and intensive radiosensitivity capacities to concurrently serve as a photothermal reagent and a radiosensitizer for hyperthermia-synergized radiotherapy (RT) against a malignant tumor. In comparison with traditional polypyrrole without noble metal doping, the innovative introduction of WCl6 not only successfully launched the polymerization of a pyrrole monomer but also endowed WPPy with additional radiosensitization. More importantly, after further decoration with an active targeted component (SP94 polypeptide), the obtained WPPy@SP94 significantly increased tumor internalization and accumulation in vitro and in vivo and induced obvious DNA damage as well as robust ROS generation under X-ray irradiation, which meanwhile synergized with strong photonic hyperthermia to effectively inhibit tumor growth by single drug injection. Moreover, such biocompatible WPPy@SP94 showed negligible adverse effects on normal cells and tissues. WPPy@SP94 developed in this study not only expands the category of polypyrrole chemical syntheses but also sheds light on WPPy@SP94-based radiosensitizers for cancer RT.

Tofacitinib as an alternative therapy for refractory intestinal Behçet's syndrome.

Background: Intestinal Behçet's syndrome is a major cause of morbidity and mortality in Behçet's syndrome. Objectives: Current treatment challenges remain in refractory intestinal Behçet's syndrome, when patients failed first and second-line therapies. Design: We reported the efficacy and safety profiles of tofacitinib in patients with moderate-severe intestinal Behçet's syndrome in a retrospective single-center study. Methods: Treatment with glucocorticoids, immunosuppressors, or even anti-TNFα monoclonal antibodies (mAbs) had previously failed. Primary outcomes were clinical remission or low disease activity and endoscopic healing. Results: We included 13 patients; 11 were administered tofacitinib 5 mg twice daily, and 2 took tofacitinib 5 mg once daily. Nine patients achieved clinical remission after a mean treatment duration of 10.1 ± 7.0 months, and the other four had low disease activity. Follow-up endoscopy was available in 11 patients: 5 had achieved mucosal healing; the other 4 achieved marked mucosal improvement. Prednisone dosage was significantly reduced, from 30 (interquartile range: 20-30) mg/d to 2.5 (interquartile range: 0-12.5) mg/d (p < 0.001). No serious adverse event was observed. Conclusion: Tofacitinib could be an efficacious and generally well-tolerated option in patients with intestinal Behçet's syndrome refractory to conventional agents, even anti-TNFα mAbs.

Rubber-Composite-Nanoparticle-Modified Epoxy Powder Coatings with Low Curing Temperature and High Toughness.

In this study, a rubber-composite-nanoparticle-modified epoxy powder composite coating with low curing temperature and high toughness was successfully fabricated. The effects of N,N-dimethylhexadecylamine (DMA) carboxy-terminated nitrile rubber (CNBR) composite nanoparticles on the microstructure, curing behavior, and mechanical properties of epoxy-powder coating were systematically investigated. SEM and TEM analysis revealed a uniform dispersion of DMA-CNBR in the epoxy-powder coating, with average diameter of 100 nm. The curing temperature of the epoxy-composite coatings had reduced almost 19.1% with the addition of 1phr DMA-4CNBR into the coating. Impact strength tests confirmed that DMA-CNBR-modified epoxy-composite coatings showed significant improvements compared with the neat EP coating, which was potentially attributed to the nanoscale dispersion of DMA-CNBR particles in epoxy coatings and their role in triggering microcracks. Other mechanical properties, including adhesion and cupping values, were improved in the same manner. In addition, thermal and surface properties were also studied. The prepared epoxy composite powder coating with the combination of low curing temperature and high toughness broadened the application range of the epoxy coatings.

A novel tumor suppressor CECR2 down regulation links glutamine metabolism contributes tumor growth in laryngeal squamous cell carcinoma.

PURPOSE: Glutamine plays an important role in tumor metabolism and progression. This research aimed to find out how Gln exert their effects on laryngeal squamous cell carcinoma (LSCC). METHODS: Cell proliferation was measured by CCK8 and EdU assay, mitochondrial bioenergetic activity was measured by mitochondrial stress tests. Gene expression profiling was revealed by RNA sequencing and validated by RT-qPCR. In LSCC patients, protein expression in tumor and adjacent tissues was examined and scored by IHC staining. RNAi was performed by stably expressed shRNA in TU177 cells. In vivo tumor growth analysis was performed using a nude mouse tumorigenicity model. RESULTS: Gln deprivation suppressed TU177 cell proliferation, which was restored by αKG supplementation. By transcriptomic analysis, we identified CECR2, which encodes a histone acetyl-lysine reader, as the downstream target gene for Gln and αKG. In LSCC patients, the expression of CECR2 in tumors was lower than adjacent tissues. Furthermore, deficiency of CECR2 promoted tumor cell growth both in vitro and in vivo, suggesting it has tumor suppressor effects. Besides, cell proliferation inhibited by Gln withdrawal could be restored by CECR2 depletion, and the proliferation boosted by αKG supplementation could be magnified either, suggested that CECR2 feedback suppressed Gln and αKG's effect on tumor growth. Transcriptomic profiling revealed CECR2 regulated the expression of a series of genes involved in tumor progression. CONCLUSION: We confirmed the Gln-αKG-CECR2 axis contributes to tumor growth in LSCC. This finding provided a potential therapeutic opportunity for the use of associated metabolites as a potential treatment for LSCC.

The phytochemical hyperforin triggers thermogenesis in adipose tissue via a Dlat-AMPK signaling axis to curb obesity.

Stimulation of adipose tissue thermogenesis is regarded as a promising avenue in the treatment of obesity. However, pharmacologic engagement of this process has proven difficult. Using the Connectivity Map (CMap) approach, we identified the phytochemical hyperforin (HPF) as an anti-obesity agent. We found that HPF efficiently promoted thermogenesis by stimulating AMPK and PGC-1α via a Ucp1-dependent pathway. Using LiP-SMap (limited proteolysis-mass spectrometry) combined with a microscale thermophoresis assay and molecular docking analysis, we confirmed dihydrolipoamide S-acetyltransferase (Dlat) as a direct molecular target of HPF. Ablation of Dlat significantly attenuated HPF-mediated adipose tissue browning both in vitro and in vivo. Furthermore, genome-wide association study analysis indicated that a variation in DLAT is significantly associated with obesity in humans. These findings suggest that HPF is a promising lead compound in the pursuit of a pharmacological approach to promote energy expenditure in the treatment of obesity.

Curcumin protects against cognitive impairments in a rat model of chronic cerebral hypoperfusion combined with diabetes mellitus by suppressing neuroinflammation, apoptosis, and pyroptosis.

BACKGROUND: Chronic cerebral hypoperfusion (CCH) is regarded as a high-risk factor for cognitive decline in vascular dementia (VaD). We have previously shown that diabetes mellitus (DM) synergistically promotes CCH-induced cognitive dysfunction via exacerbating neuroinflammation. Furthermore, curcumin has been shown to exhibit anti-inflammatory and neuroprotective activities. However, the effects of curcumin on CCH-induced cognitive impairments in DM have remained unknown. METHODS: Rats were fed with a high-fat diet (HFD) and injected with low-dose streptozotocin (STZ), followed by bilateral common carotid artery occlusion (BCCAO), to model DM and CCH in vivo. After BCCAO, curcumin (50 mg/kg) was administered intraperitoneally every two days for eight weeks to evaluate its therapeutic effects. Additionally, mouse BV2 microglial cells were exposed to hypoxia and high glucose to model CCH and DM pathologies in vitro. RESULTS: Curcumin treatment significantly improved DM/CCH-induced cognitive deficits and attenuated neuronal cell death. Molecular analysis revealed that curcumin exerted protective effects via suppressing neuroinflammation induced by microglial activation, regulating the triggering receptor expressed on myeloid cells 2 (TREM2)/toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway, alleviating apoptosis, and reducing nod-like receptor protein 3 (NLRP3)-dependent pyroptosis. CONCLUSIONS: Taken together, our findings suggest that curcumin represents a promising therapy for DM/CCH-induced cognitive impairments.

The anti-tussive, anti-inflammatory effects and sub-chronic toxicological evaluation of perilla seed oil.

BACKGROUND: Perilla seed oil (PSO) is the main constituent of perilla seeds currently being used in the food industry, however it also has great clinical potential in the regulation of lung function as a nutrition supplement because of the high content of α-linolenic acid (ALA). In this study, the pharmacological activities including anti-tussive, expectorant and anti-inflammatory effect of PSO were performed. Furthermore, the 90-day sub-chronic oral toxicity with a 30 day recovery period was evaluated in Wistar rats. RESULTS: The pharmacological studies demonstrated that PSO inhibited cough frequency induced by capsaicine in mice. PSO also inhibited the leukotriene B4 (LTB4) release from the calcium ionophore A23187-induced polymorphonuclear neutrophils (PMNs) to some extent. In this sub-chronic toxicity study, mortality, clinical signs, body weight, food consumption, hematology, serum biochemistry, urinalysis, organ weight, necropsy, and histopathology were used to evaluate the toxicity of PSO. Lower body weight and various negative impacts on liver related parameters without histopathological lesion were observed in the 16 g kg-1 groups. No clinically significant changes were discovered in the 4 g kg-1 group during the test period. CONCLUSION: In summary, PSO exhibited anti-tussive and anti-inflammatory activities in vivo and in vitro. These sub-chronic toxicity studies inferred that the 'no-observed adverse effect level' (NOAEL) of PSO in Wistar rats was determined to be 4 g kg-1 . These results may provide a safety profile and a valuable reference for the use of PSO. © 2020 Society of Chemical Industry.

Efficacy of melatonin for sleep disturbance in middle-aged primary insomnia: a double-blind, randomised clinical trial.

BACKGROUND: The aim of this study was to determine the efficacy of exogenous melatonin supplementation for sleep disturbances in patients with middle-aged primary insomnia. METHODS: This is a randomized double-blind, placebo-controlled parallel study. Participants were recruited from Tianlin community, Xuhui district, Shanghai. Ninety-seven consecutive middle-aged patients with primary insomnia were randomized to receive 3 mg fast-release melatonin (n = 51) or placebo (n = 46) for four-weeks. Objective sleep parameters tested by overnight polysomnography, subjective sleep performance and daytime somnolence obtained from the Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI) and Epworth Sleepiness Scale (ESS) were obtained at baseline and after treatment. Treatment was taken daily 1 h before bedtime. Serious adverse events and side-effects were monitored. RESULTS: Melatonin supplementation significantly decreased early wake time [-30.63min (95% CI, -53.92 to -7.34); P = 0.001] and percentage of N2 sleep [-7.07% (95% CI, -13.47% to -0.68%); P = 0.031]. However, melatonin had no significant effect on other objective sleep parameters including sleep latency, sleep efficiency, wake during the sleep and percent of N1, N3 and REM sleep. Melatonin had no effect on insomnia symptoms and severity on the PSQI [1.53(95% CI, -0.55 to 3.61); p = 0.504]; ISI [0.81 (95% CI, -2.27 to 3.88); p = 0.165] and ESS [-0.83 (95% CI, -3.53 to 1.88); p = 0.147]. No serious adverse events were reported. CONCLUSIONS: Melatonin supplementation over a four-week period is effective and safe in improving some aspects of objective sleep quality such as total sleep time, percentage of rapid eye movement and early morning wake time in middle-aged patients with insomnia. TRIAL REGISTRATION: Identifier: ChiCTR-TRC-13003997; Prospectively registered on 2 December 2013.

Decreased Synovial Fluid Biomarkers Levels Are Associated with Rehabilitation of Function and Pain in Rotator Cuff Tear Patients Following Electroacupuncture Therapy.

BACKGROUND The aim of this study was to assess inflammatory cytokines levels in synovial fluid (SF) before and after electroacupuncture (EA) treatment and to explore whether these biomarkers are associated with function of rotator cuff tear (RCT) patients. MATERIAL AND METHODS We recruited 54 patients with RCT and separated them into an EA group and a control group. The SF biomarker levels were detected at baseline and at 6-week and 6-month follow-up. The symptomatic severity was evaluated by visual analog scale (VAS), Constant-Murley score, and American Shoulder and Elbow Surgeons score (ASES). We also investigated the correlation between symptomatic severity and biomarker levels in SF of the shoulder joint. RESULTS The reductions in VAS and improved functional score (ASES and Constant-Murley score) were significantly different between the 2 groups, and SF biomarker concentrations were significantly lower in the EA group. IL-1ß levels were significantly negatively correlated with Constant-Murley score (r=-0.73, P=0.04) and ASES score (r=-0.59, P<0.001) and positively correlated with VAS scores (r=0.81, P=0.004). IL-6 levels were significantly negatively correlated with Constant-Murley score (r=-0.67, P=0.03) and positively correlated with VAS score (r=0.7, P=0.01). MMP-1 levels were significantly negatively correlated with ASES score (r=-0.57, P<0.001). CONCLUSIONS The biomarkers in SF were directly associated with shoulder pain and shoulder function in rotator cuff tear. EA, as a safe and effective conservative therapy, obviously decreased the level of inflammatory cytokines in RCT patients, accompanied by a reduction in shoulder pain and improved function.

Cedrol attenuates collagen-induced arthritis in mice and modulates the inflammatory response in LPS-mediated fibroblast-like synoviocytes.

Ginger has been used as a flavoring agent and traditional medicine for a long time in Asian countries. Pharmacological studies showed that it has antiemetic, anti-inflammatory and analgesic effects, which is attributed to its chemical constituents. The aim of the present study is to investigate the anti-rheumatoid arthritis properties of cedrol (CE) found in ginger. In an in vivo anti-RA study, CE remarkably alleviated the paw swelling and arthritis score in CE-treated CIA mice compared with the model group. The neutrophil count and the productions of TNF-α and IL-1ß were inhibited, and the expressions of Rankl, Cox-1 and Cox-2 were down-regulated at the mRNA level. Radiologic evaluation, histopathological analysis and immunohistochemistry indicated that CE ameliorated inflammatory cell infiltration, synovial hyperplasia, and bone and cartilage damage, and exhibited an immunotherapeutic effect. The MTT assay demonstrated that CE (10-10-10-5 M) had no cytotoxicity on fibroblast-like synoviocytes (FLSs), and exhibited an inhibitory effect on the proliferation of LPS-induced FLSs at concentrations of 10-6 M and 10-5 M. Mechanism research showed that the suppressed expressions of pivotal inflammatory mediators including COX-1 and COX-2 subsequently reduced the production of PGE2, thereby causing the secretions of pro-inflammatory cytokines, ultimately attenuating the progression of inflammation. Meanwhile, the reduction in the mRNA levels of Mmp-13 and Mcp-1 responsible for osteoclastogenesis resistance was detected. This illustrated that CE showed anti-rheumatoid arthritis properties via blocking the phosphorylation of ERK/MAPK and p65/NF-κB signaling pathways in LPS-activated FLSs. The current research suggested that CE is an important functional component in ginger, which may be a promising candidate drug for RA therapy.

The Impact of Preoperative Mindfulness-Based Stress Reduction on Postoperative Outcomes in Lumbar Spine Degenerative Disease: 3-Month and 12-Month Results of a Pilot Study.

BACKGROUND: We previously reported inpatient and 30-day postoperative patient-reported outcomes (PROs) of a controlled, noncrossover pilot study using preoperative mindfulness-based stress reduction (MBSR) training for lumbar spine surgery. Our goal here was to assess 3-month and 12-month postoperative PROs of preoperative MBSR in lumbar spine surgery for degenerative disease. METHODS: Intervention group participants were prospectively enrolled in a preoperative online MBSR course. A comparison standard care only group was one-to-one matched retrospectively by age, sex, surgery type, and prescription opioid use. Three-month and 12-month postoperative PROs for pain, disability, quality of life, and opioid use were compared within and between groups. Regression models were used to assess whether MBSR use predicted outcomes. RESULTS: Twenty-four participants were included in each group. At 3 months, follow-up was 87.5% and 95.8% in the comparison and intervention groups, respectively. In the intervention group, mean Patient-Reported Outcomes Measurement Information System-Physical Function (PROMIS-PF) was significantly higher, whereas mean Patient-Reported Outcomes Measurement Information System-Pain Interference (PROMIS-PI) and Oswestry Disability Index were significantly lower. The change from baseline in mean PROMIS-PF and PROMIS-PI was significantly greater than in the comparison group. At 12 months, follow-up was 58.3% and 83.3% in the comparison and intervention groups, respectively. In the intervention group, mean PROMIS-PI was significantly lower and change in mean PROMIS-PI from baseline was significantly greater. MBSR use was a significant predictor of change in PROMIS-PF at 3 months and in PROMIS-PI at 12 months. No adverse events were reported. CONCLUSIONS: Three-month and 12-month results suggest that preoperative MBSR may have pain control benefits in lumbar spine surgery.

[Effect of electroacupuncture on rehabilitation of knee joint movement after anterior cruciate ligament reconstruction].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on the rehabilitation of knee joint function after anterior cruciate ligament (ACL) reconstruction. METHODS: A total of 140 patients with ACL reconstruction were randomly divided into an observation group (58 cases recruited, 12 cases dropped out) and a control group (65 cases recruited, 5 cases dropped out). The patients in the control group were treated with routine rehabilitation treatment. The patients in the observation group, on the basis of the treatment in the control group, were treated with EA at Fengshi (GB 31), Futu (ST 32), Zusanli (ST 36), Shangjuxu (ST 37), Fenglong (ST 40), Xuanzhong (GB 39), Diji (SP 8) and Sanyinjiao (SP 6) on the affected side (2 Hz/100 Hz of dilatational wave, 2-5 mA). Each EA treatment lasted 20-30 min, twice a day for 7 days. The swelling degree (d), pain visual analogue scale (VAS), knee joint range of motion (ROM), scores of International Knee Documentation Committee (IKDC) subjective short form and scores of Lysholm were observed in the two groups 1 day, 1 month, 3 months, 6 months and 1 year after operation. RESULTS: One month and 3 months after operation, the swelling degree (d) and VAS scores in the observation group were lower than those in the control group (P<0.05); 6 months and 1 year after operation, there was no significant difference between the two groups on the swelling degree (d) and VAS scores (P>0.05). One month, 3 months, 6 months and 1 year after operation, the ROM of the knee joint in the observation group was higher than that in the control group (P<0.05), the IKDC score and Lysholm score were higher than those in the control group (P<0.05). Within one year, there were no relaxations, fractures and other related complications in the two groups. The pivot shift test, anterior drawer test and the Lachman test were all negative. CONCLUSION: EA combined with routine rehabilitation training could obviously reduce the pain of knee joint, improve the swelling degree, increase the ROM of knee joint, promote the functional recovery in patients with ACL reconstruction, which are superior to rehabilitation training alone.

Expression profile and bioinformatics analysis of COMMD10 in BALB/C mice and human.

COMMD10, a member of COMMD protein, has been proved to target p65 NF-kappaB (nuclear factor-kappaB) subunit and reduce its nuclear translocation, thereby leading to the inactivation of NF-kappaB pathway and suppression of colorectal cancer invasion and metastasis. The aim of this study is to explore its expression pattern and tissue distribution in human normal tissues and other tumor tissues and to investigate the relevant mechanism. We firstly provided the expression profile and histological distribution of COMMD10 in various BALB/c mice tissues and identified the biological distribution of COMMD10 in different kinds of human normal and tumor tissues. We verified the expression profile of COMMD10 using TCGA database. The interacting genes of COMMD10 were predicted by using STRING using. Finally, we performed database, and the microRNAs targeting COMMD10 were predicted using miRDB, miRWalk, TargetScan and microRNA. GO and KEGG pathway analyses were performed to predict the biological function of COMMD10 and its interacting genes. mRNA expression of COMMD10 showed the highest level in the lung and spleen, and the lowest level in the heart and brain. Immunohistochemistry detection revealed that COMMD10 was expressed in different tissues with different degrees and was was located mainly in the cytoplasm. Subsequently, we showed that COMMD10 displayed various degrees of expression in different human normal tissues that mainly located in cytoplasm, while COMMD10 of liver cells resided in both nucleus and cytoplasm. All the tumor tissues except breast small cell carcinoma, breast phyllodes tumor, lung adenocarcinoma, thymoma, cervical cancer and bladder urothelial carcinoma showed that COMMD10 was positive staining in cytoplasm. Kaplan-Meier plotter indicated that renal clear cell carcinoma patients with increased expression level of COMMD10 exhibited longer survival. STRING database revealed that COMMD10 had 41 interacting genes, and data from 4 different databases indicated that hsa-miR-590-3p may be the potential regulator of COMMD10. GO analysis demonstrated that COMMD10 and its interacting genes were mainly enriched in Cullin-RING ubiquitin ligase complexes, binding and transport of copper ions, the transport and steady-state maintenance of copper ions, transcription, translation and transport of proteins, and negatively regulate the activity of NF-kappaB transcription factors. KEGG pathway showed that COMMD10 and its interacting genes were mainly involved in renal cell carcinoma, HIF-1 signaling pathways, ubiquitination-mediated proteolysis, endocytosis and mineral absorption. COMMD10 may play a tumor suppressive role in renal clear cell carcinoma through the miR-590-3p-COMMD10-Cul2-RBX1-NF-κB/HIF/NRF2 pathway and regulate the chemotherapy resistance of various tumor cells to cisplatin.

The effect of supplementation of vitamin D in neurocritical care patients: RandomizEd Clinical TrIal oF hYpovitaminosis D (RECTIFY).

OBJECTIVE: Hypovitaminosis D is prevalent in neurocritical care patients, but the potential to improve patient outcome by replenishing vitamin D has not been investigated. This single-center, double-blinded, placebo-controlled, randomized (1:1) clinical trial was designed to assess the effect on patient outcome of vitamin D supplementation in neurocritical care patients with hypovitaminosis D. METHODS: From October 2016 until April 2018, emergently admitted neurocritical care patients with vitamin D deficiency (≤ 20 ng/ml) were randomized to receive vitamin D3 (cholecalciferol, 540,000 IU) (n = 134) or placebo (n = 133). Hospital length of stay (LOS) was the primary outcome; secondary outcomes included intensive care unit (ICU) LOS, repeat vitamin D levels, patient complications, and patient disposition. Exploratory analysis evaluated specific subgroups of patients by LOS, Glasgow Coma Scale (GCS) score, and Simplified Acute Physiology Score (SAPS II). RESULTS: Two-hundred seventy-four patients were randomized (intent-to-treat) and 267 were administered treatment within 48 hours of admission (as-treated; 61.2% of planned recruitment) and monitored. The mean age of as-treated patients was 54.0 ± 17.2 years (56.9% male, 77.2% white). After interim analysis suggested a low conditional power for outcome difference (predictive power 0.12), the trial was halted. For as-treated patients, no significant difference in hospital LOS (10.4 ± 14.5 days vs 9.1 ± 7.9 days, p = 0.4; mean difference 1.3, 95% CI -1.5 to 4.1) or ICU LOS (5.8 ± 7.5 days vs 5.4 ± 6.4 days, p = 0.4; mean difference 0.4, 95% CI -1.3 to 2.1) was seen between vitamin D3 and placebo groups, respectively. Vitamin D3 supplementation significantly improved repeat serum levels compared with placebo (20.8 ± 9.3 ng/ml vs 12.8 ± 4.8 ng/ml, p < 0.001) without adverse side effects. No subgroups were identified by exclusion of LOS outliers or segregation by GCS score, SAPS II, or severe vitamin D deficiency (≤ 10 ng/ml). CONCLUSIONS: Despite studies showing that vitamin D can predict prognosis, supplementation in vitamin D-deficient neurocritical care patients did not result in appreciable improvement in outcomes and likely does not play a role in acute clinical recovery.Clinical trial registration no.: NCT02881957 (clinicaltrials.gov).

Anti-inflammatory and analgesic activity based on polymorphism of cedrol in mice.

Alternate forms of drug crystals display different physicochemical properties. These include stability, dissolution rate, bioavailability and solubility, which can affect pharmacokinetics and pharmacodynamics. It is therefore important to compare the crystal forms of cedrol to obtain optimal anti-inflammatory and analgesic effects. This study, for the first time, obtained and reports three novel forms (I-III) of cedrol polymorphs. The three forms of cedrol were recrystallized from seven organic solvents by slow cooling or volatilization and identified by thermal analysis, fourier transform infrared spectroscopy, scanning electron microscopy and powder X-ray diffraction analysis. Form I originated from acetone and cyclohexane. Form II was obtained from ethanol, ethyl acetate, acetonitrile and n-hexane. Form III was recrystallized from methanol. The anti-inflammatory and analgesic activities of the three crystalline forms were evaluated by acetic acid induced writhing in mice, the hot plate method, carrageenan induced mouse paw edema models, Xylene-induced mouse ear edema models and cotton pellet-induced mouse granuloma models. Experimental results revealed that the highest performance was achieved from Form I. These findings are of great significance during the early research study of cedrol polymorphs.

Acute and sub-chronic 90-day oral toxicity study of Perilla seed oil in rodents and Beagle dogs.

Perilla seeds are used as food and traditional medicine in China. This study aimed to investigate the toxicity profile of Perilla seed oil (PSO), which is the main constituent of Perilla seeds in rodents and Beagle dogs. No significant treatment-associated toxicity or mortality was observed at PSO dosages of up to 50 g/kg and 20 g/kg in KM mice and Wistar rats, respectively, suggesting that PSO was well tolerated by the experimental rodents. Sub-chronic oral toxicity of PSO was studied in dogs at doses of 3, 6 and 12 g/kg/d for 90 days followed by a 30 day recovery period. The results indicated that the body weight increased in all-dose groups more than control group, typical of animals on diets rich in fatty acids. Treatment-related side effects, including changes in hematology and serum biochemistry parameters, histopathology of liver and lymph glands, were observed in the high and moderate-dose dogs. However, these changes disappeared after the doses were withdrawn during the recovery period, except for alteration of liver in the high-dose group. In conclusion, the "no observed adverse effect level" (NOAEL) of oral administration of PSO for 90 days in Beagle dogs was considered to be 3 g/kg/d.

Vitamin D status in cervical spondylotic myelopathy: comparison of fusion rates and patient outcome measures.

BACKGROUND: Patients undergoing elective spinal fusion have an alarming rate of vitamin D deficiency, but its impact on bone fusion and patient outcomes is unclear. We investigated the association of perioperative vitamin D levels, fusion rates, and patient-reported outcome in patients undergoing spinal fusion for cervical spondylotic myelopathy. METHODS: In this one-year, prospective, single-center observational study, serum 25-OH vitamin D levels were measured perioperatively in adult patients. Serum vitamin D levels <30 ng/mL were considered abnormal. The primary outcome measures were postoperative patient-reported outcomes (Neck Disability Index, Visual Analog Scale, EuroQol EQ-5D-3L, EQ-VAS). Secondary outcome measures were the presence of and time to solid bony fusion, controlling for Body Mass Index (BMI), age, and number of motion segments. RESULTS: Forty-one of 58 patients (71%) had laboratory-confirmed abnormal vitamin D levels. Patients with low vitamin D were younger (P<0.05) and had a higher BMI (P<0.05) than patients with adequate vitamin D, but the groups were otherwise similar. There were no differences in mean time to fusion between the two groups, but patients with low vitamin D reported more postoperative disability (P<0.05). Multivariate model analysis demonstrated an independent, significant association between normal vitamin D and lower postoperative neck disability index (P=0.05) and EQ-5D-3L (P=0.03). CONCLUSIONS: Vitamin D deficiency (<30 ng/mL) is highly prevalent in patients undergoing elective spinal fusion for cervical myelopathy. Low vitamin D levels were associated with worse patient-reported outcomes and were an independent predictor of greater disability, which suggests vitamin D supplementation may offer some benefit in these patients.

The Impact of Preoperative Mindfulness-Based Stress Reduction on Postoperative Patient-Reported Pain, Disability, Quality of Life, and Prescription Opioid Use in Lumbar Spine Degenerative Disease: A Pilot Study.

BACKGROUND: Prescription opioid medications negatively affect postoperative outcomes after lumbar spine surgery. Furthermore, opioid-related overdose death rates in the United States increased by 200% between 2000 and 2014. Thus, alternatives are imperative. Mindfulness-based stress reduction (MBSR), a mind-body therapy, has been associated with improved activity and mood in opioid-using patients with chronic pain. This study assessed whether preoperative MBSR is an effective adjunct to standard postoperative care in adult patients undergoing lumbar spine surgery for degenerative disease. METHODS: The intervention group underwent a preoperative online MBSR course. The comparison group was matched retrospectively in a 1:1 ratio by age, sex, type of surgery, and preoperative opioid use. Prescription opioid use during hospital admission and at 30 days postoperatively were compared with preoperative use. Thirty-day postoperative patient-reported outcomes for pain, disability, and quality of life were compared with preoperative patient-reported outcomes. Dose-response effect of mindfulness courses was assessed using Mindful Attention Awareness Scale scores. RESULTS: In this pilot study, 24 participants were included in each group. Most intervention patients (70.83%) completed 1 session, and the mean Mindful Attention Awareness Scale score was 4.28 ± 0.71 during hospital admission. At 30 days, mean visual analog scale back pain score was lower in the intervention group (P = 0.004) but other patient-reported outcomes did not differ. CONCLUSIONS: During hospital admission, no significant dose-response effect of mindfulness techniques was found. At 30 days postoperatively, MBSR use was associated with less back pain. Further research is needed to assess the effectiveness of preoperative MBSR on postoperative outcomes in lumbar spine surgery for degenerative disease.