Second-line antituberculosis drug exposure thresholds predictive of adverse events in multidrug-resistant tuberculosis treatment.

OBJECTIVES: This study aimed to investigate the association between drug exposure and adverse events (AEs) during the standardized multidrug-resistant tuberculosis (MDR-TB) treatment, as well as to identify predictive drug exposure thresholds. METHODS: We conducted a prospective, observational multicenter study among participants receiving standardized MDR-TB treatment between 2016 and 2019 in China. AEs were monitored throughout the treatment and their relationships to drug exposure (e.g., the area under the drug concentration-time curve from 0 to 24 h, AUC0-24 h) were analyzed. The thresholds of pharmacokinetic predictors of observed AEs were identified by boosted classification and regression tree (CART) and further evaluated by external validation. RESULTS: Of 197 study participants, 124 (62.9%) had at least one AE, and 15 (7.6%) experienced serious AEs. The association between drug exposure and AEs was observed including bedaquiline, its metabolite M2, moxifloxacin and QTcF prolongation (QTcF >450 ms), linezolid and mitochondrial toxicity, cycloserine and psychiatric AEs. The CART-derived thresholds of AUC0-24 h predictive of the respective AEs were 3.2 mg·h/l (bedaquiline M2); 49.3 mg·h/l (moxifloxacin); 119.3 mg·h/l (linezolid); 718.7 mg·h/l (cycloserine). CONCLUSIONS: This study demonstrated the drug exposure thresholds predictive of AEs for key drugs against MDR-TB treatment. Using the derived thresholds will provide the knowledge base for further randomized clinical trials of dose adjustment to minimize the risk of AEs.

Extracellular Vesicles Derived from Bone Mesenchymal Stem Cells Carrying circ_0000075 Relieves Cerebral Ischemic Injury by Competitively Inhibiting miR-218-5p and Up-regulating E3 Ubiquitin Ligase SMURF2.

Extracellular vesicle (EV)-encapsulated circRNAs have the potential role in affecting brain disorders. However, the role of circ_0000075 in cerebral ischemic injury remains unclear. Here, we tried to investigate the mechanism of bone marrow mesenchymal stem cell (BMSC)-derived EVs carrying circ_0000075 in the control of cerebral ischemic injury. Initially, a mouse model with cerebral ischemic injury was induced by middle cerebral artery occlusion (MCAO), followed by the determination of circ_0000075 expression. Then, neurons were isolated and subjected to oxygen-glucose deprivation/reperfusion. BMSCs were isolated for extraction of EVs. The correlation among circ_0000075, microRNA (miR)-218-5p, and Smad ubiquitination regulatory factor 2 (SMURF2) was detected with their roles in cerebral ischemic injury analyzed in vivo and in vitro. circ_0000075 was down-regulated in MCAO mice and engineered RVG-EVs were internalized by neurons to up-regulate circ_0000075 expression. Treatment of RVG-circ_0000075-EVs reduced brain tissue damage, increased neuronal count, and significantly curtailed apoptosis rate, suppressing cerebral ischemic injury in vitro and in vivo. miR-218-5p was targeted by circ_0000075 in neurons, which promoted SMURF2 expression. A negative correlation between SMURF2 and transcriptional regulator Yin Yang 1 (YY1) was identified. In vitro experiments further proved that circ_ 00,000 75 could down-regulate the expression of YY1 through SMURF2, and finally relieving cerebral ischemic injury. Collectively, engineered EVs delivered circ_0000075 into brain tissues and increased circ_0000075 expression, which down-regulated miR-218-5p and up-regulated SMURF2, thus alleviating cerebral ischemic injury.

Surface Modulation and Chromium Complexation: All-in-One Solution for the Cr(VI) Sequestration with Bifunctional Molecules.

The sulfidation of zero valent iron (ZVI) to an Fe@FeSx (S-ZVI) composite has been intensively explored in the ZVI field. Yet, further benefits from the FeSx coating layer are seldom realized, especially those effectively using its intrinsic physical and chemical properties for elaborate design. Here, we demonstrate that in a traditional Cr(VI) sequestration reaction, the FeSx layer displays a great utility in immobilizing molecules containing hydroxyl groups (-OH) and hence, attracting Cr(VI) complexes chelated with carboxyl organics (RCOOH). Such intermolecular attraction readily promotes the diffusion of the Cr(VI) complexes to the S-ZVI surface, affording a higher reaction rate for the Cr(VI) sequestration process. In addition, the above mechanism was used to guide a rational selection of molecules incorporating both hydroxyl and carboxyl functional groups with a proper ratio and thereby, a significantly improved reaction efficiency was achieved. Furthermore, the FeSx phase was revealed to be consumed in the reaction, acting as a supplementary reductant. This work is the first to unveil the relationship between molecules with specific functionalization and the FeSx phase, providing a general rule in choosing appropriate reaction media for Cr(VI) sequestration and related reactions.

Lingzhi or Reishi Medicinal Mushroom, Ganoderma lucidum (Agaricomycetes), Polysaccharides Suppressed Adipogenesis and Stimulated Lipolysis in HPA-v and 3T3-L1 Adipocytes.

Ganoderma lucidum polysaccharides (GLP) are one of the major bioactive components with many beneficial properties. In the present study we aimed to systematically evaluate the effects of GLP on lipid metabolism in human (HPA-v) and murine adipocytes (3T3-L1). Cell viability was assessed by MTT assay. Lipid accumulation in mature adipocytes were evaluated by ORO staining and quantified using the triglyceride (TG) assay. Lipolysis was investigated by measuring the free glycerol released in the cell culture medium after treatments. The mRNA and protein levels of key genes regulating lipid metabolism were determined by qRT-PCR and western blotting in HPA-v cells. ORO staining showed that GLP suppressed lipid accumulation similarly in both HPA-v and 3T3-L1 cells. TG assay confirmed that GLP significantly inhibited cell differentiation (p < 0.001). The lipolysis assay showed that GLP enhanced triglyceride hydrolysis in both adipocytes (p < 0.05). GLP stimulated AMPK phosphorylation, which promoted the phosphorylation of ACC1, its downstream target. qRT-PCR and western blotting showed that the genes encoding transcription factors for adipocyte differentiation (PPARγ, C/EBPα, and SREBPlc) and certain adipogenic genes (ACC1, PLIN1, and FASN) were downregulated (p < 0.05). The lipolytic gene HSL was upregulated and highly phosphorylated (activated) at mRNA and protein levels, respectively, upon GLP treatment. These results suggested that GLP possessed beneficial antiadipogenic effects and can potentially be developed into antiobesity products.

Xiaoai Jiedu Recipe Inhibits Proliferation and Metastasis of Non-Small Cell Lung Cancer Cells by Blocking the P38 Mitogen-Activated Protein Kinase (MAPK) Pathway.

BACKGROUND Lung cancer is the leading cause of cancer deaths in the world. Its major histopathological subtype is non-small cell lung cancer (NSCLC). Xiaoai Jiedu recipe (XJR) is a traditional Chinese medicine formula that can suppress growth and invasion of tumor cells. Here, we assessed the antitumor effect of XJR on NSCLC explored the underlying mechanisms. MATERIAL AND METHODS Three concentrations of XJR (low, middle, and high) were used to treat A549 cells. Cell Counting Kit-8 and colony formation assay were used to measure proliferation of A549 cells. Apoptosis was evaluated by Hoechst 33342 staining and flow cytometry. The expression of apoptosis-associated proteins was measured by Western blot analysis. Transwell and scratch wound healing assay were used to assess invasion and migration, respectively, of A549 cells. The expression of p38 MAPK pathway-associated proteins were measured using Western blot analysis. RESULTS XJR suppressed proliferation and promoted apoptosis of A549 cells, especially in the high-dose group. The expression of Bcl-2 was reduced with increasing expression of Bax, cleaved caspase-3, and cleaved caspase-9. Invasion and migration abilities of A549 cells were inhibited after XJR treatment. XJR treatment decreased the expression levels of phosphorylated p38 (p-p38), p-ERK, and p-JNK in a dose-dependent manner. CONCLUSIONS The results demonstrated that XJR can inhibit proliferation, invasion, and migration, and induce apoptosis of NSCLC by blocking the p38 MAPK pathway, which shows the potential of XJR as a new treatment of NSCLC.

Early cortical biomarkers of longitudinal transcutaneous vagus nerve stimulation treatment success in depression.

Transcutaneous vagus nerve stimulation (tVNS), a non-invasive method of brain stimulation through the auricular branch of the vagus nerve, has shown promising results in treating major depressive disorder (MDD) in several pilot studies. However, the neural mechanism by which the effect on depression might be achieved has not been fully investigated, with only a few neuroimaging studies demonstrating tVNS-induced changes in the brains of healthy volunteers. Identifying specific neural pathways, which are influenced by tVNS compared with sham in depressed individuals, as well as determining neurobiomarkers of tVNS treatment success are needed to advance the application of tVNS for MDD. In order to address these questions, we measured fMRI brain activity of thirty-eight depressed patients assigned to undergo tVNS (n = 17) or sham (n = 21) treatment for 4 weeks, during the first stimulation session. The results showed significant fMRI signal increases in the left anterior insula, revealed by a direct comparison of tVNS and sham stimulation. Importantly, the insula activation level during the first stimulation session in the tVNS group was significantly associated with the clinical improvement at the end of the four-week treatment, as indicated by the Hamilton Depression Rating Scale (HAM-D) score. Our findings suggest that anterior insula fMRI activity could serve as a potential cortical biomarker and an early predictor of tVNS longitudinal treatment success.

Effect of Kuijie Granule on the Expression of TGF-ß/Smads Signaling Pathway in Patients with Ulcerative Colitis.

The dysregulation of TGF-ß/Smads signaling pathway has been postulated to contribute to the development of ulcerative colitis (UC) and the manifestation of clinical symptoms. Kuijie Granule is a prescription medicine used clinically in China to alleviate the symptoms associated with UC. To evaluate whether the clinical benefit of Kuijie Granule is associated with TGF-ß/Smads signaling, we measured the expression levels of TGF-ß/Smads signaling proteins (TGF-ß1, TGF-ßRII, Smad2, Smad4, Smad6, and Smad7) in the intestinal mucosa of 72 patients with UC treated with Kuijie Granule for 60 days. Colonic tissues were obtained by a virtual colonoscopy guided biopsy before and after Kuijie Granule treatment followed by pathological analysis and quantitative analysis of TGF-ß/Smads using immunohistochemistry. Kuijie Granule treatment significantly improved symptoms associated with UC, which include diarrhea, mucus production, pus and blood in stool, abdominal pain and distention, and tenesmus. The clinical benefit of Kuijie Granule treatment correlated with decreased expression of TGF-ß1 and Smad7 and increased expression of TGF-ßRII and Smad4. These clinical results indicate that Kuijie Granule can alleviate the symptoms associated with UC and modulate TGF-ß/Smads signaling.

[Comparison and development of different scalp needling schools].

The literature and relevant books on the scalp needling schools were retrieved to collect the main scalp needling schools and compare the point location principles and needling techniques so as to optimize the scalp needling scheme. Currently there are ten major schools of scalp acupuncture, representing for example by JIAO Shunfa, FANG Yunpeng and YU Zhishun, etc. The principles of stimulating localization are different among the schools, in which, YU Changde's skull line localization is mainly for the treatment of cerebrovascular diseases, ZHANG Mingjiu prefers the penetrating technique for the treatment of pain and mental disorders according to traditional meridian theory, and the other schools take the cortical functions into account for the stimulating localization. Regarding needling techniques, FANG Yunpeng stresses on the deep puncture to the periosteum, and the rest school masters puncture beneath the bonnet aponeurosis. The quick rotation of needle is required in JIAO Shunfa's scalp needling, YU Changde's skull needle, International Scalp Points Standardization and the needling technique for opening brain and promotion collateral. The long-term needle retaining is required in YU Zhishun's scalp needling and ZHU Mingqing's scalp needling. It is believed that the stimulating localization principles are not standardized, the theoretic evidences are not clear and the needling depth is different among the schools. There are no standard criteria on needling angle, depth, direction, rotating speed and needle retaining time. The evidence-based medicine is recommended. Through strict scientific design, based on the clinical and experimental evidences, it is required to determine the theoretic scientific evidence of scalp acupuncture, the specificity of stimulating areas, the effective stimulating areas and quantify the needling manipulations and clarify the optimal scheme of scalp needling.

The effect of folate fortification on folic acid-based homocysteine-lowering intervention and stroke risk: a meta-analysis.

OBJECTIVE: Folate and vitamin B12 are two vital regulators in the metabolic process of homocysteine, which is a risk factor of atherothrombotic events. Low folate intake or low plasma folate concentration is associated with increased stroke risk. Previous randomized controlled trials presented discordant findings in the effect of folic acid supplementation-based homocysteine lowering on stroke risk. The aim of the present review was to perform a meta-analysis of relevant randomized controlled trials to check the how different folate fortification status might affect the effects of folic acid supplementation in lowering homocysteine and reducing stroke risk. DESIGN: Relevant randomized controlled trials were identified through formal literature search. Homocysteine reduction was compared in subgroups stratified by folate fortification status. Relative risks with 95 % confidence intervals were used as a measure to assess the association between folic acid supplementation and stroke risk. SETTING: The meta-analysis included fourteen randomized controlled trials, SUBJECTS: A total of 39 420 patients. RESULTS: Homocysteine reductions were 26·99 (sd 1·91) %, 18·38 (sd 3·82) % and 21·30 (sd 1·98) %, respectively, in the subgroups without folate fortification, with folate fortification and with partial folate fortification. Significant difference was observed between the subgroups with folate fortification and without folate fortification (P=0·05). The relative risk of stroke was 0·88 (95 % CI 0·77, 1·00, P=0·05) in the subgroup without folate fortification, 0·94 (95 % CI 0·58, 1·54, P=0·82) in the subgroup with folate fortification and 0·91 (95 % CI 0·82, 1·01, P=0·09) in the subgroup with partial folate fortification. CONCLUSIONS: Folic acid supplementation might have a modest benefit on stroke prevention in regions without folate fortification.

Ginsenoside Rg1 inhibits platelet activation and arterial thrombosis.

INTRODUCTION: Derived from the root of Panax ginseng C.A.Mey, Panax notoginsenosides (PNS) is a widely used herbal medicine to treat atherothrombotic diseases in Asian medicine. Ginsenoside Rg1 is one of the main compounds responsible for the pharmaceutical actions of PNS. As platelets play pivotal roles in atherothrombogenesis, we therefore studied the effect of Rg1 on platelet activation and its underlying mechanisms. MATERIALS AND METHODS: Human platelets are obtained from healthy subjects. Platelet activation and the inhibition of Rg1 were assessed by Born aggregometer, flow cytmetry, flow chamber and western blot. The in vivo thrombosis model was induced by 10% FeCl3 on mesenteric arterioles of wild type B57/b6 mice. RESULTS: Rg1 significantly inhibited platelet aggregation induced by thrombin, ADP, collagen and U46619, e.g., aggregation rate stimulated by 0.1UmL(-1) thrombin was decreased 46% by Rg1. Rg1 also reduced thrombin (0.1UmL(-1))-enhanced fibrinogen binding and P-selectin expression of single platelet by 81% and 66%, respectively. Rg1 affected αIIbß3-mediated outside-in signaling as demonstrated by diminished platelet spreading on immobilized fibrinogen. Rg1 also decreased the rate of clot retraction in platelet rich plasma. Furthermore, Rg1 decreased platelet adhesion on collagen surface under a shear rate correlated to the arterial flow (1000s(-1)) by approximately 70%. Western blot showed that Rg1 potently inhibited ERK phosphrylation. The in vitro findings were further evaluated in the mouse model of in vivo arterial thrombosis, and Rg1 was found to prolong the mesenteric arterial occlusion time (34.9±4.1min without and 64.3±4.9min with Rg1; p<0.01). CONCLUSIONS: Rg1 inhibits platelet activation via the inhibition of ERK pathway, and attenuates arterial thrombus formation in vivo.

Deqi sensations of transcutaneous electrical nerve stimulation on auricular points.

Deqi sensation, a psychophysical response characterized by a spectrum of different needling sensations, is essential for Chinese acupuncture clinical efficacy. Previous research works have investigated the component of Deqi response upon acupuncture on acupoints on the trunk and limbs. However, the characteristics of Deqi sensations of transcutaneous electrical nerve stimulation (TENS) on auricular points are seldom reported. In this study, we investigated the individual components of Deqi during TENS on auricular concha area and the superior scapha using quantitative measurements in the healthy subjects and depression patients. The most striking characteristics of Deqi sensations upon TENS on auricular points were tingling, numbness, and fullness. The frequencies of pressure, warmness, heaviness, and soreness were relatively lower. The dull pain and coolness are rare. The characteristics of Deqi were similar for the TENS on concha and on the superior scapha.

[Municipal wastewater treatment using a composite flocculant made of polyaluminum chloride and polydimethyldiallyammonium chloride].

A composite flocculant (denoted JYF-1), made of polyaluminum chloride (PAC) and polydimethyldiallyammonium chloride (PDMDAAC), was used in jar-tests to simulate the chemically enhanced primary treatment (CEPT) for municipal wastewater. Removal of particles, organic compounds, nitrogen and phosphorus in wastewater was investigated, and the effects of pH and surface overflow rate (SOR) on flocculation were also examined. Electrical charge and distribution of particles in wastewater were analyzed before and after flocculation. Furthermore, the flocculation mechanism and application of JYF-1 in CEPT were discussed. The results demonstrate that JYF-1 performs better than PAC under a wide pH and SOR range. When 8 mg x L(-1) JYF-1 is added, 76.72% COD and 64.31% soluble COD (SCOD) can be removed. About 90% soluble TP (STP), 80% TP and 20% TN can be removed by addition of 12 mg x L(-1) JYF-1. After flocculation, the BOD/COD ratio increases from 0.23 to 0.53, which indicates the biodegradation ability of wastewater is improved. It can be concluded that JYF-1 is a high-efficiency low-cost flocculant, which can improve outlet water quality and produce less sludge without changing the existing equipments and treating process in sewage plants.