Alpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced Cachexia.

Previous studies have shown that inhibition of TNF family member FN14 (gene: TNFRSF12A) in colon tumors decreases inflammatory cytokine expression and mitigates cancer-induced cachexia. However, the molecular mechanisms underlying the regulation of FN14 expression remain unclear. Tumor microenvironments are often devoid of nutrients and oxygen, yet how the cachexic response relates to the tumor microenvironment and, importantly, nutrient stress is unknown. Here, we looked at the connections between metabolic stress and FN14 expression. We found that TNFRSF12A expression was transcriptionally induced during glutamine deprivation in cancer cell lines. We also show that the downstream glutaminolysis metabolite, alpha-ketoglutarate (aKG), is sufficient to rescue glutamine-deprivation-promoted TNFRSF12A induction. As aKG is a co-factor for histone de-methylase, we looked at histone methylation and found that histone H3K4me3 at the Tnfrsf12a promoter is increased under glutamine-deprived conditions and rescued via DM-aKG supplementation. Finally, expression of Tnfrsf12a and cachexia-induced weight loss can be inhibited in vivo by DM-aKG in a mouse cancer cachexia model. These findings highlight a connection between metabolic stress and cancer cachexia development.

Sustained release of levobupivacaine from temperature-sensitive injectable hydrogel for long-term local anesthesia in postoperative pain management.

Postoperative pain is a major concern for most of the surgical patients, and an inadequate postoperative pain control may cause a series of complications. With an effective pain control and lesser side effects, local anesthetics are preferred for use in postoperative pain management. However, the action duration of current local anesthetics is too short to meet the requirements of postoperative analgesia. In this study, an injectable levobupivacaine (LB)-loaded thermo-sensitive hydrogel system based on biodegradable poly(D,L-lactide)-poly(ethylene glycol)-poly(D,L-lactide) (PLEL) was developed for long-acting local anesthetic, in which the soluble charged cation form of LB (LB HCl) was partly alkalified to the poorly soluble base form (LB base). This hybrid LB loaded PLEL system (hLB/PLEL) is a free flowable liquid at room temperature and changes into a semi-solid hydrogel once injection in response to the physiological temperature. Then, the dissolved LB HCl could release firstly from the hydrogel contributing to a quick work, and the insoluble LB base dissolved and released gradually as the decrease of the pH during the biodegradation of PLEL hydrogel, resulting in a long-term LB release in local. The drug release behavior, pharmacokinetic, and biocompatibility of the thermo-sensitive hLB/PLEL were studied in vitro and in vivo. The anesthetic effects of hLB/PLEL system were evaluated in the rat models of sciatic nerve block, subcutaneous infiltration anesthesia and postoperative pain as well. This hLB/PLEL system generated a significantly prolonged analgesic effect in rat models, which produced approximately 7 times longer duration than 0.75% LB HCl and effectively relieved the spontaneous pain for 3 days. In general, the presented hLB/PLEL system can not only achieve a fast-acting but also sustainably release LB to block the nerve and significantly extend the effect of local analgesia, which means a promising candidate for long-acting postoperative pain management.

Acaricidal activity of Cinnamomum cassia (Chinese cinnamon) against the tick Haemaphysalis longicornis is linked to its content of (E)-cinnamaldehyde.

BACKGROUND: The tick Haemaphysalis longicornis (Neumann) is a well-known vector of numerous pathogens of veterinary and medical importance. Various control strategies, including the use of synthetic pesticides, have been developed to control this tick species. However, demand for effective and safe alternative pesticides is increasing due to the adverse effects associated with the intensive and injudicious use of synthetic pesticides, which include undesirable effects on non-target species and environmental pollution. Hence, the acaricidal activity of the extract and the essential oil of Cinnamomum cassia (Chinese cinnamon) and their major components, and the underlying mechanisms of this activity, were evaluated against unfed larvae and nymphs of H. longicornis. METHODS: The components of the extract and essential oil of C. cassia were determined by gas chromatography-mass spectrometry, and their larvicidal and nymphicidal activity were evaluated using the larval and nymphal packet test. The underlying detoxification mechanism was elucidated by targeting in vivo esterase and monooxygenase activity, and the toxicological effect was assessed on non-target Tenebrio molitor and Harmonia axyridis by topical application in open Petri dishes. RESULTS: (E)-cinnamaldehyde was the predominant component of the extract (50.79%) and essential oil (89.95%). The 50% lethal concentration (LC50) for larvae and nymphs treated with the extract was 11.56 and 49.18 mg/mL, respectively. The essential oil, (E)-cinnamaldehyde and fenvalerate exhibited acaricidal activity, with LC50 values of 3.81, 3.15, and 0.14 mg/mL, respectively, against the larvae, and 21.31, 16.93, and 1.89 mg/mL, respectively, against the nymphs. (E)-cinnamaldehyde significantly increased esterase and monooxygenase activity in both larvae and nymphs. Unlike fenvalerate, C. cassia essential oil and (E)-cinnamaldehyde did not cause mortality of T. molitor or H. axyridis adults. CONCLUSIONS: This study demonstrates that C. cassia essential oil and (E)-cinnamaldehyde have the potential to be developed into botanical-based larvicidal and nymphicidal agents for tick control.

The Chinese Herb Codonopsis pilosula Isolate Isorhapontigenin protects against oxidative stress injury by inhibiting the activation of PI3K/Akt signaling pathway.

We investigated the effects of the Chinese herb Codonopsis pilosula isolate isorhapontigenin on antioxidant factor and the PI3K/Serine/Akt signaling pathway in Parkinson's disease. This research was, therefore, carried out to explore a possible protective mechanism of isorhamnetin in Parkinson's disease. The results support that isorhapontigenin could effectively inhibit isorhapontigenin restored myeloperoxidase + induced reduction of antioxidant levels. Also, 1-Methyl-4-phenylpyridine up-regulated the expression of phosphorylated-Akt, phosphorylated-PI3K, and phosphorylated mammalian target of rapamycin, while isorhapontigenin inhibited the expression of phosphorylated-Akt, phosphorylated-PI3K, and phosphorylated- mammalian target of rapamycin. Furthermore, LY294002 improved the antioxidant effect of isorhapontigenin in PC12 cells, and insulin-like growth factor 1 inhibited the antioxidant effect of isorhapontigenin in PC12 cells. Our results support the finding that isorhamnetin enhanced the antioxidant effect induced by 1-Methyl-4-phenylpyridine in PC12 cells by suppressing the activation of the PI3K/Akt signaling pathway.

[Assessment of efficacy of acupuncture combined with hyperbaric oxygen therapy for patients with delayed encephalopathy of CO intoxication by magnetic resonance voxel incoherent motion imaging].

OBJECTIVE: To observe the effect of acupuncture plus hyperbaric oxygen (HBO) on cerebral blood perfusion in patients with delayed encephalopathy after carbon monoxide poisoning (DEACMP). METHODS: Twenty-eight patients with DEACMP were randomly divided into acupuncture group (n=14 cases) and control group (n=14 cases). Patients of the acupuncture group were treated by using "Xingnao Kaiqiao" needling technique (specific set of acupuncture points as Yintang ï¼»EX-HN3ï¼½, Shangxing ï¼»GV23ï¼½, Baihui ï¼»GV20ï¼½, Sishenchong ï¼»EX-HN1ï¼½, Fengchi ï¼»GB20ï¼½, Taichong ï¼»LR3ï¼½, etc., and strong stimulation) combined with HBO in an air pressurized tank, and those of the control group treated by simple HBO. The treatment was conducted once a day, 5 days a week for 6 weeks. All the patients underwent head routine magnetic resonance imaging (MRI) and intravoxel incoherent motion imaging(IVIM) scan before and after the treatment. The values of pseudo-diffusion coefficient D (D*) and perfusion fraction (f) of the bilateral semi-oval centers were measured by using MITK software package to calculate the ave-rage fD* value (f×D*). The Barthel index (BI) score was used to assess the patients' daily living ability, and the correlation between parameter values was evaluated by Pearson method. RESULTS: After the treatment, the values of f, fD* and BI scores were significantly increased in both acupuncture group and control groups (P<0.05). The values of the 3 indexes were significantly higher in the acupuncture group than those in the control group (P<0.05). The values of f and fD* were positively correlated with BI score (P<0.05), with the correlation coefficients being 0.822, 0.636 and 0.601, respectively between the fD* and f, BI and f, and BI and fD*. CONCLUSION: Acupuncture combined with HBO can significantly improve the low-perfusion of bilate-ral semi-oval center and daily living ability in patients with DEACMP, being significantly superior to simple HBO therapy in the curative effect.

Botanical acaricides and repellents in tick control: current status and future directions.

Ticks are obligate blood-sucking ectoparasites and notorious as vectors of a great diversity of, in many instances, zoonotic pathogens which can cause considerable damage to animal and human health. The most commonly used approach for the control of ticks is the application of synthetic acaricides. However, the negative impacts of synthetic acaricides on the treated animals and the environment, in addition to its documented role in the development of resistance has led to the search for safer and more environmentally friendly alternative methods without compromising efficacy. An emerging promising approach for the control of ticks which has attracted much attention in recent years is the use of botanicals. Indeed, botanicals have been widely reported to show diverse effects and great potential as tick repellent and control. Although several excellent reviews have previously focused on this topic, studies on the exploration and application of botanicals to control ticks have expanded rapidly. Herein, we provide an update on the current understanding and status of botanical acaricides and repellents in tick control using recently published articles between 2017 and 2019. We also discuss the challenges and future directions in the application of botanicals in tick control, with a view of providing important clues for designing new integrated tick control methods.

[Evaluation of the efficacy of acupuncture combined with hyperbaric oxygen on delayed neuropathological sequelae after carbon monoxide poisoning by using mTI-ASL imaging].

OBJECTIVE: Quantitative assessment of white blood flow in semi-oval center of patients with delayed neuropathological sequelae (DNS) after carbon monoxide poisoning treated with acupuncture combined with hyperbaric oxygen (HBO) based on magnetic resonance multi-inversion time arterial spin labeling imaging (mTI-ASL), and to evaluate its efficacy indirectly. METHODS: Twenty-six patients with clinically diagnosed DNS were randomly divided into an observation group (13 cases) and a control group (13 cases). The conventional therapy combined with HBO were given in the control group. In the observation group,on the base of the treatment, Xingnao Kaiqiao acupuncture was applied, the main acupoints were Shuigou (GV 26), Neiguan (PC 6), Baihui (GV 20), Shangxing (GV 23), Yintang (GV 29), Sanyinjiao (SP 6) on the affected side, Sishencong (EX-HN 1), Fenglong (ST 40), Lianquan (CV 23) and Jinjin (EX-HN12) for slurred speech, Jianyu (LI 15), Waiguan (TE 5) and Shousanli (LI 10) for upper limb pain, Huantiao (GB 30), Yanglingquan (GB 34), Yinlingquan (SP 9) for lower limb pain, the treatment was given once every day, 5 days as one course, with an interval of 2 days between the course. The treatment for 6 courses was required. The conventional head MR scan, mTI-ASL and diffusion tensor imaging (DTI) scans before and 1 week after treatment were adopted, Matlab (R2014b), Mricron and Syngo.via software were adopted to measure the cerebral blood flow (CBF) and anisotropy (FA) values of the semi-oval center. The correlation between the parameters was evaluated by Pearson method. And the simple intelligent mental state examination scale (MMSE) was uesd to assess cognitive function. RESULTS: After treatment, the CBF, MMSE scores in both groups and FA values in the observation group were higher than those before treatment (P<0.05). After treatment, the CBF, FA and MMSE scores in the observation group were significantly higher than those in the control group (P<0.05). There was a positive correlation between CBF, FA and MMSE scores (P<0.05), and the correlation between CBF and MMSE was the best (r =0.822). CONCLUSION: Acupuncture combined with hyperbaric oxygen can significantly improved early white matter hypoperfusion and improved cognitive function score in patients with DNS. The curative effect is better than that of hyperbaric oxygen therapy alone. The mTI-ASL imaging can quantitatively evaluate its curative effect.

[Current state of researches on mechanisms of acupuncture in improvement of hypoxia-ischemic diseases of the central nervous system].

Acupuncture is widely used in the treatment of ischemic diseases of the central nervous system in different clinical stages and has achieved a good clinical effect. The current research showed that acupuncture can improve cerebral blood flow perfusion via increasing blood flow volume, blood flow velocity, the levels of vasomotor substances and reduction of blood viscosity and erythrocyte aggregation index. In recent years, many studies focused on the pathophysiological mechanism of acupuncture in improving cerebral ischemia via triggering the cholinergic vasodilatation, up-regulation of expression of vascular-related proteins and genes，attenuation of inflammatory reaction, etc. Currently, the methods for evaluating the effect of acupuncture are mostly noninvasive functional magnetic resonance imaging in healthy subjects. Future studies should include united selection of acupoints and acupuncture needle manipulations, more reasonable combination of different acupoints, united outcome evaluative standards, better repeatability, employment of big data, etc.

Systems Study on the Antirheumatic Mechanism of Tibetan Medicated-Bath Therapy Using Wuwei-Ganlu-Yaoyu-Keli.

In clinical practice at Tibetan area of China, Traditional Tibetan Medicine formula Wuwei-Ganlu-Yaoyu-Keli (WGYK) is commonly added in warm water of bath therapy to treat rheumatoid arthritis (RA). However, its mechanism of action is not well interpreted yet. In this paper, we first verify WGYK's anti-RA effect by an animal experiment. Then, based on gene expression data from microarray experiments, we apply approaches of network pharmacology to further reveal the mechanism of action for WGYK to treat RA by analyzing protein-protein interactions and pathways. This study may facilitate our understanding of anti-RA effect of WGYK from perspective of network pharmacology.

[Effects of naoxintong capsule on the inflammation and prognosis in borderline lesion coronary heart disease patients].

OBJECTIVE: To study the effects of Naoxintong Capsule (NC) on the inflammation and long-term prognosis in the borderline lesion coronary heart disease patients. METHODS: A total of 240 coronary heart disease patients with angina symptoms and accompanied with borderline lesion coronary heart disease (with the diameter stenosis in critical 50% -70%) by means of coronary angiography or multislice computed tomography coronary angiography were recruited. These patients were randomly assigned to the conventional treatment group (including nitrate, beta blockers, anti-platelet, anticoagulation, angiotensin converting enzyme inhibitors, and so on) and the NC treatment group (treated the same way as those for the conventional treatment group and NC). All patients were treated for 12 months. The occurrence of cardiovascular events was observed after treatment. The inflammatory factors in serum [interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and high sensitive C reaction protein (hs-CRP)], matrix metalloproteinases-9 (MMP-9), blood lipids and blood sugar, liver and kidney functions were measured before and after treatment. RESULTS: After 12 months of treatment, the incidence of angina pectoris patients (6.67% vs 15.83%, P < 0.05) and hospitalization due to acute coronary syndrome (ACS) attacks (4.17% vs 10.83%) was significantly lower in the NC treatment group than in the conventional treatment group. There was no statistical difference in the serum levels of IL-6, TNF-alpha, hs-CRP, and MMP-9 between the two groups before treatment (P > 0.05). After 12 months of treatment, serum levels of IL-6, TNF-alpha, hs-CRP, and MMP-9 were significantly lower when compared with before treatment in the same group (P < 0.05). Besides, the serum levels of IL-6, TNF-alpha, hs-CRP, and MMP-9 were significantly lower in the NC group than in the conventional treatment group (P < 0.05). By means of Logistic regression analysis we found that the post-treatment MMP-9 level and IL-6 level were independent risk factors influencing the recurrence of angina pectoris. CONCLUSIONS: NC could alleviate the inflammation. Long-term administration of NC could reduce the recurrence of angina pectoris and decrease the incidence of ACS attack in borderline lesion coronary heart disease patients. The post-treatment MMP-9 level and IL-6 level were independent risk factors influencing the recurrence of angina pectoris.