Site-Selective Photosynthesis of Ag-AgCl@Au Nanomushrooms for NIR-II Light-Driven O2- and O2•--Evolving Synergistic Photothermal Therapy against Deep Hypoxic Tumors.

Light-driven endogenous water oxidation has been considered as an attractive and desirable way to obtain O2 and reactive oxygen species (ROS) in the hypoxic tumor microenvironment. However, the use of a second near-infrared (NIR-II) light to achieve endogenous H2O oxidation to alleviate tumor hypoxia and realize deep hypoxic tumor phototherapy is still a challenge. Herein, novel plasmonic Ag-AgCl@Au core-shell nanomushrooms (NMs) were synthesized by the selective photodeposition of plasmonic Au at the bulge sites of the Ag-AgCl nanocubes (NCs) under visible light irradiation. Upon NIR-II light irradiation, the resulting Ag-AgCl@Au NMs could oxidize endogenous H2O to produce O2 to alleviate tumor hypoxia. Almost synchronously, O2 could react with electrons on the conduction band of the AgCl core to generate superoxide radicals (O2•-)for photodynamic therapy. Moreover, Ag-AgCl@Au NMs with an excellent photothermal performance could further promote the phototherapy effect. In vitro and in vivo experimental results show that the resulting Ag-AgCl@Au NMs could significantly improve tumor hypoxia and enhance phototherapy against a hypoxic tumor. The present study provides a new strategy to design H2O-activatable, O2- and ROS-evolving NIR II light-response nanoagents for the highly efficient and synergistic treatment of deep O2-deprived tumor tissue.

Acupuncture and herbal moxibustion for the treatment of 'BiQiu' (allergic rhinitis symptoms) in a Hong Kong Chinese medicine clinic: a randomized controlled trial.

BACKGROUND: Allergic rhinitis (AR) is a common disease. No evidence is available for the clinical application of acupuncture and moxibustion for the management of AR symptoms in Hong Kong. This study aimed to evaluate the clinical effectiveness of acupuncture with or without herbal moxibustion on relieving AR symptoms in the Hong Kong population. METHODS: A single-centre, randomized, assessor-blinded, controlled trial with three parallel arms (acupuncture alone, acupuncture combined with herbal moxibustion treatment and waitlist) was designed. Groups with acupuncture treatment received treatment 3 times per week for a total of 12 sessions in 4 weeks. Acupuncture combined with herbal moxibustion treatment group received herbal moxibustion once per week for a total of 4 sessions over 4 weeks in addition to acupuncture treatment. Participants in the waitlist group received no treatment. All patients received advice on healthy lifestyle, diet, and exercise. RESULTS: Ninety-six subjects were recruited and allocated randomly (1:1:1) into three study groups. Compared to the waitlist group, both treatment groups demonstrated statistically significant decreases in TNSS and RQLQ at the end of treatment as well as after follow-up period (all P < 0.01). However, there was no statistically differences between these two treatment groups. There was no difference in the change of total IgE levels among study groups before or after the treatment. Only one patient reported adverse effects with herbal moxibustion treatment, and no adverse effects were found in others. CONCLUSIONS: This study supports that acupuncture could help relieve AR symptoms, but no evidence on additional treatment effect of herbal moxibustion was found.Trial registration ChiCTR-INR-16010047 registered on November 25, 2016.

Biyuanling suppresses the toluene-2, 4-diisocyanate induced allergic rhinitis in guinea pigs.

Allergic rhinitis (AR), one of the common diseases of the upper respiratory system, is associated with high risk of nasopharyngeal carcinoma. Biyuanling Granules (BLG), a formulated preparation of traditional Chinese medicine, has been used in China for treatment of AR for more than a decade; however, its exact action against allergic rhinitis and the mechanism involved remain unclear. In this study, we studied the effects of BLG on allergic rhinitis induced by toluene-2, 4- diisocyanate (TDI) in guinea pigs. The anti-AR effects of BLG were evaluated by behavior observations, histological examinations of the nasal tissues stained with hematoxylin and eosin staining (H&E), immunohistochemical analyses of pulmonary surfactant associated protein (SP), Bcl-2 Associated X Protei (Bax), tumor necrosis factor (TNF-α) and vascular cell adhesion molecule-1 (VCAM-1) in the nasal mucosa, and serum tests of interleukin-4 (IL-4) and human SARS-specific immunoglobulin (SIgE) levels. We observed that in the AR-positive animals treated with BLG, the symptom scores were significantly higher (P < 0.01), the nasal mucosa edemas and inflammatory infiltrates were significantly alleviated (P < 0.01) and the serum IL-4 and SIgE levels were significantly decreased (P < 0.05) as compared with the control group. Immunohistochemical examinations of the nasal mucosa demonstrated that the expressions of TNF-α, SP and VCAM-1 were significantly decreased (P < 0.01), whereas Bax expression was increased in the BLG treatment groups (P < 0.05). These results indicate that BLG can effectively suppress the TDI-induced AR, and that the protective effects of BLG were associated with reductions of TNF-α, SP and VCAM-1, and an elevation of Bax, suggesting that BLG exerts its AR-suppressive effects through inhibition of inflammatory response.

Astragalin Reduces Hexokinase 2 through Increasing miR-125b to Inhibit the Proliferation of Hepatocellular Carcinoma Cells in Vitro and in Vivo.

Astragalin (ASG) can be found in a variety of food components. ASG exhibits cytotoxic effects on several different types of malignant cells. However, its effects on hepatocellular carcinoma (HCC) cells and the underlying molecular mechanisms have remained to be fully elucidated. Here, we revealed that ASG remarkably suppressed the proliferation of HCC cells. In HCC cells, ASG inhibited glucose glycolysis and promoted oxidative phosphorylation, resulting in a surge of reactive oxygen species (ROS). Mechanistically, ASG suppressed the expression of hexokinase 2 (HK2). This event was indispensible for ASG-mediated metabolic reprogramming, ROS accumulation, and subsequent growth arrest. Our further investigations unveiled that ASG repressed HK2 expression via increasing miR-125b. In vivo experiments showed that gavage of ASG decreased the proliferation of Huh-7 HCC xenografts in nude mice and inhibited the growth of transplanted H22 HCC cells in Kunming mice. Declined HCC tumor growth in vivo was associated with boosted miR-125b and reduced expression of HK2 in tumor tissues. Collectively, our results demonstrated that ASG is able to suppress the proliferation of HCC cells both in vitro and in vivo. Inhibition of HK2 through upregulating miR-125b and subsequent metabolic reprogramming is implicated in the antiproliferative effects of ASG on HCC cells.

Role of Arcuate Nucleus in the Regulation of Feeding Behavior in the Process of Altitude Acclimatization in Rats.

Liu, Xiang-Wen, Jie Yin, Qi-Sheng Ma, Chu-Chu Qi, Ji-Ying Mu, Lang Zhang, Li-Ping Gao, and Yu-Hong Jing. Role of arcuate nucleus in the regulation of feeding behavior in the process of altitude acclimatization in rats. High Alt Med Biol. 18:234-241, 2017.-Highly efficient energy utilization and metabolic homeostasis maintenance rely on neuromodulation. Altitude exposure is known to stimulate neuroendocrine systems to respond to acute hypoxia and adaptive acclimatization. However, limited data on how the adaptive regulation of the arcuate nucleus performs in the process of altitude acclimatization are available. In the present study, male Sprague Dawley rats were transported to Huashixia, Qinghai (with an altitude of 4400 m) from Xian (with an altitude of 300 m) by air; rats were consistently raised in Xian as control. Food uptake and body weight were measured consecutively after being subjected to high-altitude condition. Contents of plasma leptin and ghrelin were analyzed by the Enzyme Linked Immunosorbent Assay (ELISA) Kits. Brain coronal sections were obtained, and neuropeptide Y (NPY), proopiomelanocotin (POMC), and c-fos immunoreactivity in arcuate nucleus were observed. Arcuate nucleus was isolated from the hypothalamus, and the mRNA of NPY and POMC were measured by quantitative real-time polymerase chain reaction. Our results showed both food consumption and body weight decreased in the high plateau compared with rats raised in the low-altitude condition. Plasma leptin increased at the early stage, and ghrelin decreased at a later stage after reaching the high plateau. The peak of c-fos immunoreactivity in the arcuate nucleus was at day 3 after reaching the high plateau. The expression level of NPY increased, and POMC decreased in the arcuate nucleus at day 7 after reaching the high plateau compared with the plain control group. These results indicate that the arcuate nucleus of hypothalamus performs an important function in regulating feeding behavior during altitude acclimatization. Our study suggested that altitude acclimation is regulated by the hypothalamus that received leptin and ghrelin signals to response by its microcircuit, including NPY- and POMC-neurons in the arcuate nucleus.

Autophagy plays beneficial effect on diabetic encephalopathy in type 2 diabetes: studies in vivo and in vitro.

OBJECTIVES: The hypothalamus regulates metabolism and feeding behavior by perceiving the levels of peripheral insulin. However, little is known about the hypothalamic changes after aberrant metabolism. In this study, we investigated the changes of insulin and autophagy relevant signals of hypothalamus under diabetes mellitus. METHODS: C57B/L mice were injected with low-dose streptozotocin (STZ) and fed with high-fat diet to induce type 2 diabetes mellitus. In vitro, PC12 cells were treated with oleic acid to mimic lipotoxicity. RESULTS: Results showed that the cholesterol level in the hypothalamus of the diabetic mice was higher than that of the normal mice. The expression of insulin receptors and insulin receptor substrate-1 were downregulated and the number of Fluoro-Jade C positive cells significantly increased in the hypothalamic arcuate nucleus of the diabetic mice. Furthermore, Upregulation of mammalian target of rapamycin (mTOR) and downregulation of LC 3II were obvious in the hypothalamus of the diabetic mice. In vitro, results showed that high-lipid caused PC12 cell damage and upregulated LC3 II expression. Pretreatment of cells with 3-methyladenine evidently downregulated LC3 II expression and aggravated PC12 cell death under high lipid conditions. By contrast, pretreatment of cells with rapamycin upregulated LC3 II expression and ameliorated PC12 cell death caused by lipotoxicity. CONCLUSION: These results demonstrate that autophagy activation confers protection to neurons under aberrant metabolism and that autophagy dysfunction in the hypothalamus occurs in the chronic metabolic disorder such as T2DM.

Placebo acupuncture in an acupuncture clinical trial. How good is the blinding effect?

The purpose of this study was to critically look at the validity of the "placebo procedures" used in acupuncture studies. Twenty healthy volunteers were recruited and blinded either to genuine acupuncture or to "placebo procedures", and they were checked to ascertain whether they could differentiate genuine punctures from placebo punctures. Each volunteer received paired procedures on three separate occasions. Each paired procedure included one genuine puncture and a placebo procedure. Three placebo procedures, that is, sham points, superficial puncture, and puncturing through a special device, were used. Two standard acupuncture points were used: Hegu (LI-4) in the hand and Zusanli (ST-36) in the leg. Among the 18 participants who completed all three tests, 16 correctly recognized genuine punctures. Sham sites in the hand and the leg were detected by 15 and nine of the participants, respectively. Superficial punctures in the hand and the leg were recognized by 10 and nine of the participants, respectively. A special device, a foam cylinder that hid the distal needle, worked best because 15 and 16 of the participants were deceived when the device was used at an acupoint in the hand and the leg, respectively. No significant differences were noted between those who had had past experience with acupuncture and those who had not. Sham sites and superficial punctures appeared not to have a placebo function because 50-83% of the participants were able to immediately recognize their false nature. Using a hidden device worked much better.

Brain aging and AD-like pathology in streptozotocin-induced diabetic rats.

OBJECTIVE: Numerous epidemiological studies have linked diabetes mellitus (DM) with an increased risk of developing Alzheimer's disease (AD). However, whether or not diabetic encephalopathy shows AD-like pathology remains unclear. RESEARCH DESIGN AND METHODS: Forebrain and hippocampal volumes were measured using stereology in serial coronal sections of the brain in streptozotocin- (STZ-) induced rats. Neurodegeneration in the frontal cortex, hypothalamus, and hippocampus was evaluated using Fluoro-Jade C (FJC). Aß aggregation in the frontal cortex and hippocampus was tested using immunohistochemistry and ELISA. Dendritic spine density in the frontal cortex and hippocampus was measured using Golgi staining, and western blot was conducted to detect the levels of synaptophysin. Cognitive ability was evaluated through the Morris water maze and inhibitory avoidant box. RESULTS: Rats are characterized by insulin deficiency accompanied with polydipsia, polyphagia, polyuria, and weight loss after STZ injection. The number of FJC-positive cells significantly increased in discrete brain regions of the diabetic rats compared with the age-matched control rats. Hippocampal atrophy, Aß aggregation, and synapse loss were observed in the diabetic rats compared with the control rats. The learning and memory of the diabetic rats decreased compared with those of the age-matched control rats. CONCLUSIONS: Our results suggested that aberrant metabolism induced brain aging as characterized by AD-like pathologies.

Stereoselective reduction of 1-o-isopropyloxygenipin enhances its neuroprotective activity in neuronal cells from apoptosis induced by sodium nitroprusside.

Genipin is a Chinese herbal medicine with both neuroprotective and neuritogenic activity. Because of its unstable nature, efforts have been to develop more stable genipin derivatives with improved biological activities. Among the new compounds reported in the literature, (1R)-isopropyloxygenipin (IPRG001) is a more stable but less active compound compared with the parent, genipin. Here, two new IPRG001 derivatives generated by stereoselective reduction of the C6 =C7 double bond were synthesized. The 1R and 1S isomers of (4aS,7S,7aS)-methyl-7-(hydroxymethyl)-1-isopropoxy-1,4a,5,6,7,7a-hexahydrocyclopenta[c]pyran-4-carboxylate (CHR20 and CHR21) were shown to be very stable both in high-glucose cell culture medium and in mice serum at 37 °C. Evaluation using an MTT assay and Hoechst staining showed that CHR20 and CHR21 promote the survival of rat adrenal pheochromocytoma (PC12) and retinal neuronal (RGC-5) cells from injury induced by sodium nitroprusside (SNP). The neuroprotective effects of CHR20 and CHR21 were greater than both isomers of IPRG001, the parent compounds. These results indicate that reduction of 1-O-isopropyloxygenipin enhances its neuroprotective activity without affecting its stability.

Acupuncture: Complications are preventable not adverse events.

If adverse effects are understood as "something that happened unexpectedly" while receiving drug treatment, there is no difference between adverse effects and complications. However, acupuncture is a process different from the use of drugs. While acupuncture procedures should not be taken for granted as safe, complications causing harm are usually, according to the authors, the result of negligence, and should be differentiated from other adverse effects. Harmful complications noted consisted of bleeding and damage to the tissues and organs under the puncture sites. Adverse effects consisted of symptomatology like fainting and other systemic disturbances difficult to explain. In a study of acupuncture complications and adverse effects in 2000 procedures conducted by experienced professional acupuncturists in a research institution, it was found that complications did not occur, and adverse events happened infrequently. Attempts were made to explain the causes of adverse effects. Now that acupuncture is being widely incorporated into medical practice, a good understanding of adverse effects and complications would be necessary and helpful.

Acupuncture in the treatment of rheumatoid arthritis: a double-blind controlled pilot study.

BACKGROUND: In planning a randomized controlled trial of acupuncture, we conducted a pilot study using validated outcome measures to assess the feasibility of the protocol, and to obtain preliminary data on efficacy and tolerability of 3 different forms of acupuncture treatment as an adjunct for the treatment of chronic pain in patients with Rheumatoid arthritis (RA). METHODS: The study employs a randomized, prospective, double-blind, placebo-controlled trial to evaluate the effect of electroacupuncture (EA), traditional Chinese acupuncture (TCA) and sham acupuncture (Sham) in patients with RA. All patients received 20 sessions over a period of 10 weeks. Six acupuncture points were chosen. Primary outcome is the changes in the pain score. Secondary outcomes included the changes in the ACR core disease measures, DAS 28 score and the number of patients who achieved ACR 20 at week 10. RESULTS: From 80 eligible patients, 36 patients with mean age of 58 +/- 10 years and disease duration of 9.3 +/- 6.4 years were recruited. Twelve patients were randomized to each group. Twelve, 10 and 7 patients from the EA, TCA and Sham group respectively completed the study at 20 weeks (p < 0.03); all except one of the premature dropouts were due to lack of efficacy. At week 10, the pain score remained unchanged in all 3 groups. The number of tender joints was significantly reduced for the EA and TCA groups. Physician's global score was significantly reduced for the EA group and patient's global score was significantly reduced for the TCA group. All the outcomes except patient's global score remained unchanged in the Sham group. CONCLUSION: This pilot study has allowed a number of recommendations to be made to facilitate the design of a large-scale trial, which in turn will help to clarify the existing evidence base on acupuncture for RA. TRIAL REGISTRATION: ClinicalTrials.gov NCT00404443.