Effect of surface modification on the distribution of magnetic nanorings in hepatocellular carcinoma and immune cells.

Magnetic nanomaterial-mediated magnetic hyperthermia is a localized heating treatment modality that has been applied to treat aggressive cancer in clinics. In addition to being taken up by tumor cells to function in cancer therapy, magnetic nanomaterials can also be internalized by immune cells in the tumor microenvironment, which may contribute to regulating the anti-tumor immune effects. However, there exists little studies on the distribution of magnetic nanomaterials in different types of cells within tumor tissue. Herein, ferrimagnetic vortex-domain iron oxide nanorings (FVIOs) with or without the liver-cancer-targeting peptide SP94 have been successfully synthesized as a model system to investigate the effect of surface modification of FVIOs (with or without SP94) on the distribution of tumor cells and different immune cells in hepatocellular carcinoma (HCC) microenvironment of a mouse. The distribution ratio of FVIO-SP94s in tumor cells was 1.3 times more than that of FVIOs. Immune cells in the liver tumor microenvironment took up fewer FVIO-SP94s than FVIOs. In addition, myeloid cells were found to be much more amenable than lymphoid cells in terms of their ability to phagocytose nanoparticles. Specifically, the distributions of FVIOs/FVIO-SP94s in tumor-associated macrophages, dendritic cells, and myeloid-derived suppressor cells were 13.8%/12%, 3.7%/0.9%, and 6.3%/1.2%, respectively. While the distributions of FVIOs/FVIO-SP94s in T cells, B cells, and natural killer cells were 5.5%/0.7%, 3.0%/0.7%, and 0.4%/0.3%, respectively. The results described in this article enhance our understanding of the distribution of nanomaterials in the tumor microenvironment and provide a strategy for rational design of magnetic hyperthermia agents that can effectively regulate anti-tumor immune effects.

Intracellular Magnetic Hyperthermia Enables Concurrent Down-Regulation of CD47 and SIRPα To Potentiate Antitumor Immunity.

Harnessing the potential of tumor-associated macrophages (TAMs) to engulf tumor cells offers promising avenues for cancer therapy. Targeting phagocytosis checkpoints, particularly the CD47-signal regulatory protein α (SIRPα) axis, is crucial for modulating TAM activity. However, single checkpoint inhibition has shown a limited efficacy. In this study, we demonstrate that ferrimagnetic vortex-domain iron oxide (FVIO) nanoring-mediated magnetic hyperthermia effectively suppresses the expression of CD47 protein on Hepa1-6 tumor cells and SIRPα receptor on macrophages, which disrupts CD47-SIRPα interaction. FVIO-mediated magnetic hyperthermia also induces immunogenic cell death and polarizes TAMs toward M1 phenotype. These changes collectively bolster the phagocytic ability of macrophages to eliminate tumor cells. Furthermore, FVIO-mediated magnetic hyperthermia concurrently escalates cytotoxic T lymphocyte levels and diminishes regulatory T cell levels. Our findings reveal that magnetic hyperthermia offers a novel approach for dual down-regulation of CD47 and SIRPα, reshaping the tumor microenvironment to stimulate immune responses, culminating in significant antitumor activity.

Electroacupuncture with intermittent wave stimulation as rehabilitation approach for chronic Bell's palsy: a randomized controlled trial.

PURPOSE: To evaluate the effectiveness and safety of electroacupuncture (EA) using intermittent wave stimulation in enhancing facial symmetry and nerve function in chronic Bell's palsy patients. METHODS: A 6-week assessor-blinded, randomized trial followed by an 18-week observational period was conducted. Sixty individuals with chronic Bell's palsy, showing no signs of recovery after 12 months, were equally divided to receive either 18 sessions of EA using intermittent wave stimulation or Transcutaneous Electrical Stimulation (TES), administered thrice weekly over 6 weeks. The primary outcome measure was the change in the total facial nerve index (TFNI) score from baseline to Week 6, with secondary outcomes including TFNI scores at Weeks 12 and 24, as well as the change in Sunnybrook Facial Grading System (SFG) score from baseline to Week 6, and SFG scores at Weeks 12 and 24. RESULTS: The EA group showed a significant improvement, with a mean total facial nerve index score increase of 24.35 (4.77) by Week 6 compared with 14.21 (5.12) in the Transcutaneous Electrical Stimulation group (P<.001). This superiority persisted during the 24-week follow-up. While no significant difference was observed in the Sunnybrook Facial Grading System score change from baseline to Week 6, variations were noted at Weeks 12 and 24. No major adverse effects were reported. CONCLUSION: EA with intermittent wave stimulation notably enhanced facial symmetry in chronic Bell's palsy patients over Transcutaneous Electrical Stimulation by Week 6, maintaining this edge throughout the follow-up.

Effects of aromatherapy on fatigue, quality of sleep and quality of life in patients with inflammatory bowel disease: A feasibility study.

BACKGROUND: Fatigue, poor sleep quality and poor quality of life (QoL) are recognised as common problems for patients with inflammatory bowel disease (IBD). This study aimed to evaluate feasibility and effect of aromatherapy on these problems in patients with IBD. METHODS: Seventy IBD patients from a tertiary hospital in China were randomly assigned to an intervention group and a control group. During the 8-week intervention, the intervention group received aromatherapy through the skin and by inhalation, and the control group received routine nursing care. All patients were administered questionnaires at two sessions-the Multidimensional Fatigue Inventory, the Inflammatory Bowel Disease Questionnaire and the Pittsburgh Sleep Quality Index-before and after the intervention. The clinical trial registration number is ChiCTR2100045889. RESULTS: Postintervention fatigue and sleep problems were relieved in the intervention group compared with the control group (P < 0.05). Moreover, QoL scores improved significantly in the intervention group (P < 0.05). CONCLUSION: These results suggested that aromatherapy may be an effective complementary treatment method to relieve fatigue and sleep problems and improve quality of life in IBD patients.

Magnetic hyperthermia induces effective and genuine immunogenic tumor cell death with respect to exogenous heating.

Immunogenic cell death (ICD) can improve the therapeutic effects of cancer immunotherapy by initiating adaptive immune responses. Unlike the exogenous hyperthermia modality in clinics, magnetic hyperthermia (MH) is characterized by an iron oxide nano-agent acting as a heating source and the effects induced by heating acting at the intracellular region. However, the immunological effects of endogenous heating generated during MH and exogenous heating, and the difference in damage-associated molecular pattern (DAMP) emissions correlating with the ICD are unclear; whether MH elicits genuine ICD remains unknown. Herein, we have identified 10 distinct DAMP correlates of ICD induced by intracellular MH, and found that only heat shock proteins 70/90 were expressed after water bath heating (exogenous hyperthermia) in human triple-negative breast cancer (TNBC) MDA-MB-231 cells, murine TNBC 4T1 cells, and surgically resected specimens of ductal breast cancer from patients. In vivo vaccination assays were performed in immunocompetent BALB/c mice. The results demonstrated that MH with endogenous heating could stimulate the genuine ICD on 4T1 cells and achieved optimal therapeutic effects on 4T1 tumors, whereas exogenous heating under the same conditions failed to elicit these effects. These findings with regard to the MH induced genuine ICD with high efficiency are critical for the development of safe and effective therapeutics to amplify the therapeutic responses of cancer immunotherapy.

Putrescine Treatment Delayed the Softening of Postharvest Blueberry Fruit by Inhibiting the Expression of Cell Wall Metabolism Key Gene VcPG1.

The postharvest shelf life of blueberries is very short at room temperature owing to softening, which reduces their edible value. Putrescine (Put) plays an important role in maintaining the firmness and prolonging the storage time of fruits. Therefore, we investigated the relationship between Put and the cell wall metabolism and their roles in the postharvest softening of blueberry. Harvested blueberry fruit was immersed in 1 mM Put aqueous solution for 10 min. After treatment, the blueberries were stored at 20 ± 0.5 °C and 80% relative humidity for 10 days. The results show that Put delayed the softening of the blueberries. Compared to the control, the blueberry fruit treated with Put showed higher levels of firmness and protopectin. Moreover, the activity and expression levels of the cell wall metabolism enzymes were markedly inhibited by the Put treatment, including polygalacturonase (PG), ß-galactosylase (ß-Gal), and ß-glucosidase (ß-Glu). The Put treatment promoted the expression of the Put synthesis gene VcODC and inhibited the expression of the Put metabolism gene VcSPDS. Further tests showed that the fruit firmness decreased significantly after the overexpression of VcPG1, which verified that VcPG1 is a key gene for fruit softening. The key transcription factors of fruit softening were preliminarily predicted and the expressions were analyzed, laying a foundation for the subsequent study of transcriptional regulation. These results indicate that Put delays the softening of postharvest blueberry by restraining the cell wall metabolism and maintaining the fruit firmness.

[CO2 laser moxibustion for endometriosis related pelvic pain of cold coagulation and blood stasis: a randomized controlled trial].

OBJECTIVE: To observe the clinical therapeutic effect of CO2 laser moxibustion on endometriosis related pelvic pain of cold coagulation and blood stasis. METHODS: A total of 76 patients with endometriosis related pelvic pain of cold coagulation and blood stasis were randomized into a laser moxibustion group and a sham laser moxibustion group, 38 cases in each group. In the laser moxibustion group, moxibustion was applied at bilateral Zigong (EX-CA 1) using CO2 laser moxibustion instrument. In the sham laser moxibustion group, the manipulation of moxibustion was same as the laser moxibustion group, without laser output. The treatment was given once every other day, 30 min each time, 3 times a week for 4 weeks in both groups. Before and after treatment and follow-up of 3 months after treatment, the scores of Gracely box scale (GBS) and visual analogue scale (VAS) were observed, the usage of non-steroidal anti-inflammatory drug for the duration of the treatment and the average days of taking drugs were recorded in both groups. RESULTS: Compared before treatment, the GBS and VAS scores were decreased after treatment and during follow-up in the laser moxibustion group (P<0.05), while those in the sham moxibustion group had no significant differences (P>0.05). Compared with the sham moxibustion group, the GBS and VAS scores were decreased after treatment and during follow-up (P<0.05), the cases and average days of taking drugs were less in the laser moxibustion group (P<0.05). CONCLUSION: CO2 laser moxibustion can improve the pain symptom in patients with endometriosis related pelvic pain of cold coagulation and blood stasis, and reduce the use of analgesic drugs.

Comparing the efficacy of two different temperature stimulation in warm acupuncture on acute low back pain: A randomized controlled trial.

BACKGROUND: Warm acupuncture, a combination of the mechanical stimulation of acupuncture and thermal stimulation of moxibustion, is commonly used in treating acute low back pain (LBP). This trial aimed to compare the efficacy of stronger (above 43°C) and weaker (above 40°C) heat stimulation in warm acupuncture on the function and pain in patients with acute LBP due to lumbosacral disc degeneration (LDD). METHODS: One hundred and fifty-nine adults were randomly assigned to receive warm acupuncture treatment with silver needle (SvN) or with stainless steel needle (SSN) (1:1). Both groups received a 3-week therapy with 3 sessions per week. The primary outcome was the modified Oswestry Disability Index at week 4. The secondary outcomes included average pain, three physical sign tests and adverse events. Participants were followed up at week 16 and week 28 after randomization. RESULTS: The LBP related disability and pain intensity significantly relieved more in the SvN warm acupuncture group than in the SSN group, in both the short and long term (p<0.001). The between-groups difference in physical signs showed statistical significance only in the short term (p = 0.024), but not in long term (p = 0.081; p = 0.069). CONCLUSION: Compared with warm acupuncture with stainless-steel needle at above 40°C, warm acupuncture with silver needle at above 43°C relieved more disability and pain in patients with acute LBP due to LDD. STUDY REGISTRATION: Chinese Clinical Trial Registry (ChiCTR1800019051).

Sini Decoction Ameliorates Colorectal Cancer and Modulates the Composition of Gut Microbiota in Mice.

Sini Decoction (SND), as a classic prescription of Traditional Chinese Medicine (TCM), has been proved to be clinically useful in cardiomyopathy and inflammatory bowel diseases. However, the role and mechanism of SND in colitis-associated cancer remains unclear. This study aims to evaluate the effect of SND on colorectal cancer(CRC) symptoms and further explore the changes of gut microbes mediated by SND extract in azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CRC mice through 16 S rRNA sequencing. Our results indicated that treatment with SND extract could ameliorate the tumors' malignant degree by decreasing tumor number and size. Also, the expression levels of Cyclooxygenase 2 and Mucin-2, which are typical CRC biomarkers, were reduced compared to the CRC group. In the meantime, SND extract can upregulate CD8+ T lymphocytes' expression and Occludin in the colonic mucosal layer. Besides, SND inhibited the expression of CD4+ T cells and inflammatory cytokines in CRC tissue. According to bioinformatics analysis, SND extract was also suggested could modulate the gut microbial community. After the SND treatment, compared with the CRC mice model, the number of pathogenic bacteria showed a significant reduction, including Bacteroides fragilis and Sulphate-reducing bacteria; and SND increased the relative contents of the beneficial bacteria, including Lactobacillus, Bacillus coagulans, Akkermansia muciniphila, and Bifidobacterium. In summary, SND can effectively intervene in colorectal cancer development by regulating intestinal immunity, protecting the colonic mucosal barrier, and SND can change the intestinal microbiota composition in mice.

Stereoselective and Divergent Construction of ß-Thiolated/Selenolated Amino Acids via Photoredox-Catalyzed Asymmetric Giese Reaction.

Sulfur and selenium occupy a distinguished position in biology owing to their redox activities, high nucleophilicity, and acyl transfer capabilities. Thiolated/selenolated amino acids, including cysteine, selenocysteine, and their derivatives, play critical roles in regulating the conformation and function of proteins and serve as an important motif for peptide design and bioconjugation. Unfortunately, a general and concise method to attain enantiopure ß-thiolated/selenolated amino acids remains an unsolved problem. Herein, we present a photoredox-catalyzed asymmetric method for the preparation of enantiopure ß-thiolated/selenolated amino acids using a simple chiral auxiliary, which controls the diastereoselectivity of the key alkylation step and acts as an orthogonal protecting group in the subsequent peptide synthesis. Our protocol can be used to prepare a wide range of ß-thiolated/selenolated amino acids on a gram scale, which would otherwise be difficult to obtain using conventional methods. The effect of our chemistry was further highlighted and validated through the preparation of a series of peptidyl thiol/selenol analogues, including cytochrome c oxidase subunit protein 7C and oxytocin.

Ethylene plays an important role in the softening and sucrose metabolism of blueberries postharvest.

We studied the effects of ethylene on softening and sucrose metabolism in postharvest blueberry fruit by examining the responses of fruit firmness, cell wall polysaccharides, cell wall enzymes, four key genes of cell wall degradation and metabolism, enzyme activities, and five key genes of sucrose metabolism to exogenous ethylene treatments. Ethylene was found to accelerate blueberry softening, as it promoted the degradation of pectin and expression of pectinesterase (PE) and polygalacturonase (PG). Sucrose catabolism was accelerated with fruit softening, while sucrose content, sucrose phosphate synthase (SPS) activity were positively correlated with the loss of fruit firmness. Exogenous ethylene treatments promoted sucrose metabolism by inhibiting the expression of VcSPS1 and VcNIN2 and stimulating the expression of VcSS1 and VcCWINV1. These results indicate that ethylene plays an important role in fruit softening and sucrose metabolism of blueberry at 20 °C, and there may be a link between sucrose metabolism and fruit softening.

Evaluation of clinical efficacy of silver-needle warm acupuncture in treating adults with acute low back pain due to lumbosacral disc herniation: study protocol for a randomized controlled trial.

BACKGROUND: As a common cause of low back pain, lumbosacral disc herniation (LDH) is usually dealt with using non-surgical interventions. In the face of concerns about prescription opioid abuse, alternative and complementary treatments may be promising, among which silver-needle warm acupuncture is considered as an upgrading option for its potential anti-inflammatory and strong analgesic effect for patients with chronic pain. In this proposed study, we aim to assess its clinical efficacy in comparison with conventional stainless steel filiform-needle warm acupuncture. METHODS/DESIGN: This is a randomized, two-armed, patient- and assessor-blinded trial. One hundred and sixty eligible patients recruited from December 2018 to June 2020 in three centers will be assigned for warm acupuncture treatment with either stainless steel filiform or silver needles. Nine sessions of 20-min treatment will be conducted during 3 consecutive weeks. Assessments with instruments including the Oswestry Disability Index, the visual analog scale, and the Japanese Orthopedic Association Back Pain Evaluation Questionnaire will be performed at four time points to explore the difference of clinical efficacy between two groups. DISCUSSION: If the results show that participants treated with silver-needle warm acupuncture gain a greater improvement in terms of pain intensity, physical function, and quality of life, this study is expected to offer reliable evidence to widely push this treatment for LDH in clinical practice. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1800019051 . Registered on 24 October 2018.

The effect of ethylene absorbent treatment on the softening of blueberry fruit.

The potential of ethylene absorbent (EA) to delay softening of 'Lanfeng' blueberry (Vaccinium spp.) fruit in conjunction with cold storage was evaluated. The fruit quality was evaluated after 60 days of storage at 0 °C again kept at 20 °C, with or without EA. Changes in quality attributes and ethylene biosynthesis and fruit softening indicators were assessed. The results indicated that EA treatment inhibited fruit softening, reduced weight loss and decay, and prevented the loss of total phenolic content. It also decreased the fruit ethylene production by inhibiting 1-aminocyclopropane-1-carboxylic acid oxidase and 1-aminocyclopropane-1- carboxylic acid synthase activities, whilst maintaining firmness by hampering cell wall-degrading enzyme activities, especially after more than 30 days of cold storage. In conclusion, EA treatment can inhibit the softening of harvested blueberry fruit during storage at 0 °C and shelf life after cold storage. After being refrigerated for more than 30 days at 0 °C, the EA has a good effect on blueberries storage.

Moxibustion treatment for diarrhea-predominant irritable bowel syndrome: study protocol for a randomized controlled trial.

BACKGROUND: Irritable bowel syndrome (IBS) is a worldwide disease with high morbidity. The effect of current treatment with Western medicine is not satisfactory. Although moxibustion treatment is widely used for gastrointestinal diseases, randomized controlled trials on the use of this treatment for IBS are limited. This study aims to evaluate the clinical efficacy and safety of moxibustion treatment in patients with diarrhea-predominant irritable bowel syndrome (IBS-D). METHODS/DESIGN: A multi-center, randomized, single-blind and placebo-controlled trial is employed. 104 cases will be divided into two groups: (1) a mild-warm moxibustion group in which moxa stick is 3-5 cm away from acupuncture points and the skin temperature is maintained at 43 ± 1 °C; and (2) a placebo moxibustion group in which moxa stick is 8-10 cm away from acupuncture points and the skin temperature is maintained at 37 ± 1 °C. Moxibustion is performed on bilateral ST25 and ST36 in the two groups for 30 min each time, three times a week for 6 weeks. The patients are followed up at the 12th and 18th weeks. Adequate relief is used as a primary outcome measure; IBS symptom severity score, Bristol stool form scale, IBS quality-of-life questionnaire, and hospital anxiety and depression scale are used as secondary outcome measures. DISCUSSION: This study aims to demonstrate the safety and efficacy of moxibustion treatment for IBS-D, which may validate moxibustion as an effective therapy for treating IBS-D. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02421627 (8 April 2015).

[Active Crohn's disease treated with acupuncture and moxibustion:a randomized controlled trial].

OBJECTIVE: To observe the effects and safety of clinical common symptoms of active Crohn's disease at the mild and moderate stages treated with acupuncture and moxibustion. METHODS: One hundred and two patients were randomly divided into an observation group and a control group, 51 cases in each one. Herb-partition moxibustion and acupuncture were used in the observation group. Herbal cakes with Huanglian (coptis chinensis), Fuzi (radix aconiti carmichaeli), Rougui (cinnamomum cassia), Muxiang (radices saussureae), Honghua (carthamus tinctorious), Danshen (the root of red-rooted salvia) and Danggui (angelica sinensis) as the main ingredients were used on Tianshu (ST 25), Qihai (CV 6) and Zhongwan (CV 12); acupuncture was used at Zusanli (ST 36), Shangjuxu (ST 37), Sanyinjiao (SP 6), Taixi (KI 3), Gongsun (SP 4) and Taichong (LR 3). Bran-partition moxibustion and shallow acupuncture were applied in the control group. Wheat bran-partition moxibustion in the shape of cake was implemented on the same acupoints as the observation group; shallow acupuncture was used 1~2 cm next to the acupoints. Treatment was given three times a week for 12 weeks, 36 times totally. Clinical effects of eight symptoms were evaluated by TCM symptom score, and the symptoms included abdominal pain (degree, frequency, time), diarrhoea (number, shape and frequency), fatigue, anorexia, borborygmus andflatus, fear of cold, soreness and weakness of waist and knees, tenesmus. RESULTS: After 12-week treatment, the eight symptoms were improved apparently (all P<0.05), with the scores of abdominal pain (degree, frequency, time), diarrhoea (shape and frequency), fatigue and anorexia in the observation group decreasing more obviously (all P<0.01). There was no statistical significance about the other symptom scores between the two groups (all P>0.05). CONCLUSIONS: Herb-partition moxibustion combined with acupuncture achieve safety and efficacy for mild and moderate Crohn's disease, and can improve the clinical common symptoms. Furthermore, their effects on abdominal pain (degree, frequency, time), diarrhoea (shape and frequency), fatigue and anorexia are better than those of bran-partition moxibustion and shallow acupuncture.

Moxibustion and Acupuncture Ameliorate Crohn's Disease by Regulating the Balance between Th17 and Treg Cells in the Intestinal Mucosa.

Previous studies have demonstrated that acupuncture is beneficial to patients with Crohn's disease (CD), but the mechanism underlying its therapeutic effects remains unclear. To identify the mechanism by which acupuncture treats CD, the balance between Th17 and Treg cells was assessed in CD patients. In this study, Ninety-two CD patients were randomly and equally assigned to a treatment group that were treated with herb-partitioned moxibustion and acupuncture or a control group with wheat bran-partitioned moxibustion and superficial acupuncture. The effect of these treatments on Th17 and Treg cells and their related molecular markers in the intestinal mucosa were detected before (week 0) and after (week 12) treatment. The results suggested that the ratio of Th17 and Treg cells was significantly decreased after treatment and that the levels of IL-17 and RORγt in the intestinal mucosa were obviously reduced, while the expression of FOXP3 was increased after treatment in both groups. In the treatment group, the expression of these molecules was more markedly regulated than the control group. In conclusion, moxibustion and acupuncture have been shown to regulate the ratio of Th17 and Treg cells in the intestinal mucosa of CD patients and restore the balance between these immune cell subsets.