Far-Infrared Therapy Based on Graphene Ameliorates High-Fat Diet-Induced Anxiety-Like Behavior in Obese Mice via Alleviating Intestinal Barrier Damage and Neuroinflammation.

The consumption of a high-fat diet (HFD) has been implicated in the etiology of obesity and various neuropsychiatric disturbances, including anxiety and depression. Compelling evidence suggests that far-infrared ray (FIR) possesses beneficial effects on emotional disorders. However, the efficacy of FIR therapy in addressing HFD-induced anxiety and the underlying mechanisms remain to be elucidated. Here, we postulate that FIR emitted from a graphene-based therapeutic device may mitigate HFD-induced anxiety behaviors. The graphene-FIR modify the gut microbiota in HFD-mice, particularly by an enriched abundance of beneficial bacteria Clostridiaceae and Erysipelotrichaceae, coupled with a diminution of harmful bacteria Lachnospiraceae, Anaerovoracaceae, Holdemania and Marvinbryantia. Graphene-FIR also improved intestinal barrier function, as evidenced by the augmented expression of the tight junction protein occludin and G protein-coupled receptor 43 (GPR43). In serum level, we observed the decreased free fatty acids (FFA), lipopolysaccharides (LPS), diamine oxidase (DAO) and D-lactate, and increased the glucagon-like peptide-2 (GLP-2) levels in graphene-FIR mice. Simultaneously, inflammatory cytokines IL-6, IL-1ß, and TNF-α manifested a decrease subsequent to graphene-FIR treatment in both peripheral and central system. Notably, graphene-FIR inhibited over expression of astrocytes and microglia. We further noticed that the elevated the BDNF and decreased TLR4 and NF-κB expression in graphene-FIR group. Overall, our study reveals that graphene-FIR rescued HFD-induced anxiety via improving the intestine permeability and the integrity of blood-brain barrier, and reduced inflammatory response by down regulating TLR4/NF-κB inflammatory pathway.

Activated Carbon nanoparticles Loaded with Metformin for Effective Against Hepatocellular Cancer Stem Cells.

Introduction: Hepatocellular cancer stem cells (CSCs) play crucial roles in hepatocellular cancer initiation, development, relapse, and metastasis. Therefore, eradication of this cell population is a primary objective in hepatocellular cancer therapy. We prepared a nanodrug delivery system with activated carbon nanoparticles (ACNP) as carriers and metformin (MET) as drug (ACNP-MET), which was able to selectively eliminate hepatocellular CSCs and thereby increase the effects of MET on hepatocellular cancers. Methods: ACNP were prepared by ball milling and deposition in distilled water. Suspension of ACNP and MET was mixed and the best ratio of ACNP and MET was determined based on the isothermal adsorption formula. Hepatocellular CSCs were identified as CD133+ cells and cultured in serum-free medium. We investigated the effects of ACNP-MET on hepatocellular CSCs, including the inhibitory effects, the targeting efficiency, self-renewal capacity, and the sphere-forming capacity of hepatocellular CSCs. Next, we evaluated the therapeutic efficacy of ACNP-MET by using in vivo relapsed tumor models of hepatocellular CSCs. Results: The ACNP have a similar size, a regular spherical shape and a smooth surface. The optimal ratio for adsorption was MET: ACNP=1:4. ACNP-MET could target and inhibit the proliferation of CD133+ population and decrease mammosphere formation and renewal of CD133+ population in vitro and in vivo. Conclusion: These results not only suggest that nanodrug delivery system increased the effects of MET, but also shed light on the mechanisms of the therapeutic effects of MET and ACNP-MET on hepatocellular cancers. ACNP, as a good nano-carrier, could strengthen the effect of MET by carrying drugs to the micro-environment of hepatocellular CSCs.

Network pharmacology and pharmacological evaluation for deciphering novel indication of Sishen Wan in insomnia treatment.

BACKGROUND: Insomnia is the most frequent sleep disorder worldwide and is a prominent risk factor for mental and physical health deterioration. The clinical application of common pharmacological treatments for insomnia is far from satisfactory due to their various adverse effects. In recent years, drugs developed from natural herbs have become potential alternative therapies for insomnia. Sishen Wan (SSW), a traditional Chinese medicine (TCM) used for centuries to treat diarrheal disease, consists of multiple neurologically active herbs with sleep-regulating potential that may have therapeutic effects on insomnia. However, its hypnotic and sleep-regulating effects have not been evaluated in clinical practice or laboratory experiments. PURPOSE: To investigate the anti-insomnia effects of SSW and explore its possible mechanisms using preclinical models. STUDY DESIGN AND METHODS: The sedative effect of the SSW formula was investigated using network pharmacology analysis that was validated using various pharmacological approaches, including the evaluation of locomotor activity (LMA), pentobarbital-induced sleep time, and electroencephalography/electromyogram (EEG/EMG)-based sleep profiling in normal rats. Several animal models of insomnia, including sleep deprivation, serotonin depletion, and cage-changing models, have been used to further assess the anti-insomnia effects of SSW. Furthermore, the potential underlying mechanisms of action of SSW were predicted using bioinformatics methods and verified using in vivo and in silico experiments. RESULTS: The results showed that SSW reduced LMA and prolonged pentobarbital-induced sleep time in a dose-dependent manner, which was consistent with the increase in non-rapid eye movement (NREM) sleep in normal rats, indicating a solid sedative effect. In animal models of insomnia, SSW alleviated sleep disturbance by increasing NREM sleep time, shortening NREM sleep latency, and inhibiting sleep fragmentation, suggesting a possible curative effect of SSW on insomnia. Finally, through functional enrichment analysis and in vivo and in silico experiments, 5-HT1A was identified as the key target of the anti-insomnia effect of SSW. Moreover, (S)-propranolol, nuciferine, zizyphusine, and N,N-dimethyl-5-methoxytryptamine may be the active compounds of SSW responsible for its anti-insomnia effect. CONCLUSION: This study extended the possible indication scope for SSW, which provides a potential therapeutic TCM that may be used for insomnia treatment, as well as a reference scheme for the discovery of novel indications of TCM.

Xinyang Tablet attenuates chronic hypoxia-induced right ventricular remodeling via inhibiting cardiomyocytes apoptosis.

BACKGROUND: Hypoxia-induced pulmonary hypertension (HPH) is one of the fatal pathologies developed under hypobaric hypoxia and eventually leads to right ventricular (RV) remodeling and RV failure. Clinically, the mortality rate of RV failure caused by HPH is high and lacks effective drugs. Xinyang Tablet (XYT), a traditional Chinese medicine exhibits significant efficacy in the treatment of congestive heart failure and cardiac dysfunction. However, the effects of XYT on chronic hypoxia-induced RV failure are not clear. METHODS: The content of XYT was analyzed by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS). Sprague-Dawley (SD) rats were housed in a hypobaric chamber (equal to the parameter in altitude 5500 m) for 21 days to obtain the RV remodeling model. Electrocardiogram (ECG) and hemodynamic parameters were measured by iWorx Acquisition & Analysis System. Pathological morphological changes in the RV and pulmonary vessels were observed by H&E staining and Masson's trichrome staining. Myocardial apoptosis was tested by TUNEL assay. Protein expression levels of TNF-α, IL-6, Bax, Bcl-2, and caspase-3 in the RV and H9c2 cells were detected by western blot. Meanwhile, H9c2 cells were induced by CoCl2 to establish a hypoxia injury model to verify the protective effect and mechanisms of XYT. A CCK-8 assay was performed to determine the viability of H9c2 cells. CoCl2-induced apoptosis was detected by Annexin-FITC/PI flow cytometry and Hoechst 33,258 staining. RESULTS: XYT remarkably improved RV hemodynamic disorder and ECG parameters. XYT attenuated hypoxia-induced pathological injury in RV and pulmonary vessels. We also observed that XYT treatment decreased the expression levels of TNF-α, IL-6, Bax/Bcl-2 ratio, and the numbers of myocardial apoptosis in RV. In H9c2 myocardial hypoxia model, XYT protected H9c2 cells against Cobalt chloride (CoCl2)-induced apoptosis. We also found that XYT could antagonize CoCl2-induced apoptosis through upregulating Bcl-2, inhibiting Bax and caspase-3 expression. CONCLUSIONS: We concluded that XYT improved hypoxia-induced RV remodeling and protected against cardiac injury by inhibiting apoptosis pathway in vivo and vitro models, which may be a promising therapeutic strategy for clinical management of hypoxia-induced cardiac injury.

Melatonin pretreatment prevents propofol-induced sleep disturbance by modulating circadian rhythm in rats.

Postoperative sleep disorder frequently occurs in patients after surgery. Sleep disturbance aggravates pain, anxiety, and delirium, which is an important risk factor for poor recovery. Circadian rhythm disorder induced by general anesthesia plays important role in postoperative sleep disorders. A large number of clinical studies have shown that various forms and duration of general anesthesia can lead to postoperative sleep disorders. In this study, the effect of prolonged propofol anesthesia on biological rhythm was comprehensively evaluated by wireless physiological telemetry system, and the therapeutic effect of exogenous melatonin pretreatment was further investigated. The results showed that prolonged propofol anesthesia had significant impacts on the circadian rhythm of sleep, body temperature, locomotor activity and endogenous melatonin secretion within 24 h following anesthesia, resulting in diminished oscillation amplitude. In hypothalamus, the expression of circadian factor PER and CRY were inhibited by propofol, possibly through activation of CAMK-CREB signaling pathway. Post-translational factors GSK-3ß, SIRT1, AMPK were also involved in the regulation of circadian factors after propofol anesthesia. Melatonin pretreatment could restore circadian rhythm process by regulating circadian factor expression through post-translational modulation and prohibit the over-synthesis of melatonin in pineal gland. This study verified the effects of anesthetics on circadian rhythm and further evaluated the potential therapeutic effect of melatonin on postoperative circadian rhythm and sleep disorders.

Association of non-thyroidal illness syndrome with interleukin-6 and interleukin-10 in critically ill children with sepsis / 中国当代儿科杂志

OBJECTIVE@#To study the incidence rate of non-thyroidal illness syndrome (NTIS) in critically ill children with or without sepsis and the association of NTIS with interleukin-6 (IL-6) and interleukin-10 (IL-10).@*METHODS@#A retrospective analysis was performed on the medical data of 97 children with sepsis (sepsis group) and 80 non-sepsis children with bacterial infection (non-sepsis group). The correlations of IL-6 and IL-10 with the thyroid function parameters triiodothyronine (T3), thyroxine (T4), and thyroid stimulating hormone (TSH) were analyzed.@*RESULTS@#There were no significant differences in age and sex between the sepsis and non-sepsis groups (P>0.05). Compared with the non-sepsis group, the sepsis group had a significantly higher Sequential Organ Failure Assessment score, a significantly longer length of hospital stay, and a significantly higher rate of use of ventilator (P0.05), but the pooled analysis of the two groups showed that IL-6 level was negatively correlated with T3 and T4 levels (P<0.001).@*CONCLUSIONS@#Children with sepsis have a higher incidence rate of NTIS than those without sepsis. The high level of IL-6 may be associated with the development of NTIS.

Effect of continuous hemofiltration on inflammatory mediators and hemodynamics in children with severe hand, foot and mouth disease / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To investigate the effect of continuous veno-venous hemofiltration (CVVH) on inflammatory mediators in children with severe hand, foot and mouth disease (HFMD), and to investigate its clinical efficacy.</p><p><b>METHODS</b>A total of 36 children with stage IV HFMD were enrolled and randomly divided into conventional treatment group and CVVH group (n=18 each). The children in the CVVH group were given CVVH for 48 hours in addition to the conventional treatment. The levels of interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α) and lactic acid in peripheral venous blood, heart rate, blood pressure, and left ventricular ejection fraction were measured before treatment and after 24 and 48 hours of treatment.</p><p><b>RESULTS</b>After 24 hours of treatment, the conventional treatment group had a significantly reduced serum IL-2 level (P<0.01), and the CVVH treatment group had significantly reduced serum levels of IL-2, IL-6, IL-10, and TNF-α (P<0.05). After 48 hours of treatment, both groups had significantly reduced serum levels of IL-2, IL-6, IL-10, and TNF-α (P<0.01), and the CVVH group had significantly lower levels of these inflammatory factors than the conventional treatment group (P<0.01). After 48 hours of treatment, heart rate, systolic pressure, and blood lactic acid level were significantly reduced, and left ventricular ejection fraction was significantly increased in both groups, and the CVVH group had significantly greater changes in these indices except systolic pressure than the conventional treatment group (P<0.01).</p><p><b>CONCLUSIONS</b>CVVH can effectively eliminate inflammatory factors, reduce heart rate and venous blood lactic acid, and improve heart function in children with severe HFMD.</p>