Brain Delivery of Biomimetic Phosphorus Dendrimer/Antibody Nanocomplexes for Enhanced Glioma Immunotherapy via Immune Modulation of T Cells and Natural Killer Cells.

Fully mobilizing the activities of multiple immune cells is crucial to achieve the desired tumor immunotherapeutic efficacy yet still remains challenging. Herein, we report a nanomedicine formulation based on phosphorus dendrimer (termed AK128)/programmed cell death protein 1 antibody (aPD1) nanocomplexes (NCs) that are camouflaged with M1-type macrophage cell membranes (M1m) for enhanced immunotherapy of orthotopic glioma. The constructed AK128-aPD1@M1m NCs with a mean particle size of 160.3 nm possess good stability and cytocompatibility. By virtue of the decorated M1m having α4 and ß1 integrins, the NCs are able to penetrate the blood-brain barrier to codeliver both AK128 with intrinsic immunomodulatory activity and aPD1 to the orthotopic glioma with prolonged blood circulation time. We show that the phosphorus dendrimer AK128 can boost natural killer (NK) cell proliferation in peripheral blood mononuclear cells, while the delivered aPD1 enables immune checkpoint blockade (ICB) to restore the cytotoxic T cells and NK cells, thus promoting tumor cell apoptosis and simultaneously decreasing the tumor distribution of regulatory T cells vastly for improved glioma immunotherapy. The developed nanomedicine formulation with a simple composition achieves multiple modulations of immune cells by utilizing the immunomodulatory activity of nanocarrier and antibody-mediated ICB therapy, providing an effective strategy for cancer immunotherapy.

Bioactive Phosphorus Dendrimers as a Universal Protein Delivery System for Enhanced Anti-inflammation Therapy.

Nanocarrier-based cytoplasmic protein delivery offers opportunities to develop protein therapeutics; however, many delivery systems are positively charged, causing severe toxic effects. For enhanced therapeutics, it is also of great importance to design nanocarriers with intrinsic bioactivity that can be integrated with protein drugs due to the limited bioactivity of proteins alone for disease treatment. We report here a protein delivery system based on anionic phosphite-terminated phosphorus dendrimers with intrinsic anti-inflammatory activity. A phosphorus dendrimer termed AK-137 with optimized anti-inflammatory activity was selected to complex proteins through various physical interactions. Model proteins such as bovine serum albumin, ribonuclease A, ovalbumin, and fibronectin (FN) can be transfected into cells to exert their respective functions, including cancer cell apoptosis, dendritic cell maturation, or macrophage immunomodulation. Particularly, the constructed AK-137@FN nanocomplexes display powerful therapeutic effects in acute lung injury and acute gout arthritis models by integrating the anti-inflammatory activity of both the carrier and protein. The developed anionic phosphite-terminated phosphorus dendrimers may be employed as a universal carrier for protein delivery and particularly utilized to deliver proteins and fight different inflammatory diseases with enhanced therapeutic efficacy.

Unsymmetrical Low-Generation Cationic Phosphorus Dendrimers as a Nonviral Vector to Deliver MicroRNA for Breast Cancer Therapy.

The development of nonviral dendritic polymers with a simple molecular backbone and great gene delivery efficiency to effectively tackle cancer remains a great challenge. Phosphorus dendrimers or dendrons are promising vectors due to their structural uniformity, rigid molecular backbones, and tunable surface functionalities. Here, we report the development of a new low-generation unsymmetrical cationic phosphorus dendrimer bearing 5 pyrrolidinium groups and one amino group as a nonviral gene delivery vector. The created AB5-type dendrimers with simple molecular backbone can compress microRNA-30d (miR-30d) to form polyplexes with desired hydrodynamic sizes and surface potentials and can effectively transfect miR-30d to cancer cells to suppress the glycolysis-associated SLC2A1 and HK1 expression, thus significantly inhibiting the migration and invasion of a murine breast cancer cell line in vitro and the corresponding subcutaneous tumor mouse model in vivo. Such unsymmetrical low-generation phosphorus dendrimers may be extended to deliver other genetic materials to tackle other diseases.

The Effect of Astragalus on Humoral and Cellular Immune Response: A Systematic Review and Meta-Analysis of Human Studies.

INTRODUCTION: Astragalus is used in traditional Chinese medicine for immune system disorders. Its effect on immune system function is evaluated in multiple studies. The objective of this systematic review and meta-analysis was to evaluate the effect of Astragalus on humoral and cellular immune response in human studies. METHODS: A comprehensive search of electronic databases was conducted to identify relevant studies published up to April 2023. Studies that assessed the impact of Astragalus on humoral and cellular immune markers were included. The data were extracted, and a random-effects meta-analysis was performed to determine the overall effect size. Subgroup analyses were conducted based on outcome measures. RESULTS: A total of 19 studies, including 1,094 human participants, were included in the meta-analysis. The analysis of humoral immune markers revealed a significant reduction in proinflammatory cytokines, including IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ, following Astragalus intervention (SMD -2.8765, 95% CI: -3.2385 to -2.5145, p < 0.0001). In the cellular immunity domain, Astragalus was found to significantly increase CD3 levels and the CD4/CD8 ratio (SMD 2.4629, 95% CI: 1.9598; 2.9661). Subgroup analyses based on outcome measures supported these findings. However, substantial heterogeneity was observed among the included studies. CONCLUSION: This systematic review and meta-analysis provide evidence supporting the immunomodulatory effects of Astragalus on humoral and cellular response. Astragalus demonstrated a significant reduction in proinflammatory cytokines and an enhancement of cellular immune markers, suggesting its potential as a therapeutic agent for immune-related disorders.Astragalus wird in der traditionellen chinesischen Medizin bei Erkrankungen des Immunsystems eingesetzt. Seine Wirkung auf das Immunsystem ist in mehreren Studien untersucht worden. Das Ziel dieser systematischen Übersichtsarbeit und Metaanalyse ist es, die Wirkung von Astragalus auf die humorale und zelluläre Immunantwort in Studien am Menschen zu untersuchen.Eine umfassende Suche in elektronischen Datenbanken wurde durchgeführt, um einschlägige Studien zu finden, die bis April 2023 veröffentlicht wurden. Eingeschlossen wurden Studien, die die Auswirkung von Astragalus auf Marker der humoralen und zellulären Immunantwort untersuchten. Die Daten wurden extrahiert und eine Random-Effects-Metaanalyse durchgeführt, um die Gesamt-Effektstärke zu ermitteln. Subgruppenanalysen wurden basierend auf Zielgrößen durchgeführt.Insgesamt 19 Studien mit 1'094 menschlichen Teilnehmern wurden in die Metaanalyse eingeschlossen. Die Analyse der humoralen Immunmarker ergab eine signifikante Abnahme proinflammatorischer Zytokine, darunter IL-2, IL-4, IL-6, IL-10, TNF-α und IFN-γ, nach Anwendung von Astragalus (SMD ­2.8765; 95%-KI: −3.2385, −2.5145; p < 0.0001). Bei der zellulären Immunität zeigte Astralagus eine signifikante Erhöhung der CD3-Konzentration und des CD4/CD8-Quotienten (SMD 2.4629; 95%-KI: 1.9598, 2.9661). Die Subgruppenanalysen nach Zielgrößen bestätigten diese Ergebnisse. Zwischen den eingeschlossenen Studien bestand jedoch erhebliche Heterogenität.Diese systematische Übersichtsarbeit und Metaanalyse liefert Belege für die immunmodulatorischen Effekte von Astragalus auf die humorale und zelluläre Immunantwort. Astragalus zeigte eine signifikante Abnahme proinflammatorischer Zytokine und eine Verbesserung von Markern der zellulären Immunität, was auf sein Potenzial als Therapeutikum bei immunvermittelten Störungen hindeutet.

[Research progress on chemical constituents of Schisandra chinensis and its effect on nonalcoholic fatty liver disease].

Schisandra chinensis, a traditional Chinese medicinal herb, is rich in chemical constituents, including lignans, triterpenes, polysaccharides, and volatile oils. Clinically, it is commonly used to treat cardiovascular, cerebrovascular, liver, gastrointestinal, and respiratory diseases. Modern pharmacological studies have shown that S. chinensis extract and monomers have multiple pharmacological activities in lowering liver fat, alleviating insulin resistance, and resisting oxidative stress, and have good application prospects in alleviating nonalcoholic fatty liver disease(NAFLD). Therefore, this study reviewed the research progress on chemical constituents of S. chinensis and its effect on NAFLD in recent years to provide references for the research on S. chinensis in the treatment of NAFLD.

Non-occupational lead poisoning associated with traditional Chinese medicine: A case report.

Introduction: Traditional Chinese medicine has a long history and is widely popular in China because of its safety and small side effects. In Chinese families, people believe that the combination of traditional Chinese and Western medicine is more effective, and in terms of conditioning and health care, they tend to rely on traditional Chinese medicine. However, the toxic and side effects of traditional Chinese medicine, especially heavy metal poisoning, should not be ignored. Patient concerns: A case of non-occupational lead poisoning caused by long-term use of traditional Chinese medicine. Diagnosis: A 21-year-old man with severe colic periumbilical pain was referred to our hospital. Through careful inquiry of his medical history, we found that he had been taking traditional Chinese medicine to treat facial acne in the past year. His test results showed anemia, liver damage, blood lead concentration of 1,268.4 µg/L, and bone marrow smear showed basophilic stippling erythrocyte. The patient was diagnosed with "lead poisoning." Interventions: The patient was given treatment with lead driving. Outcomes: The patient recovered after treatment. Conclusion: We found that lead poisoning in patients taking traditional Chinese medicine has been reported from time to time. Through consulting the data, we summarized the most common drugs leading to lead poisoning, and reviewed the pathogenesis and common clinical manifestations of lead poisoning. Because lead poisoning is easy to be misdiagnosed, we should ask more carefully about the past history and drug history of patients in order to make timely diagnosis and treatment.

[Exploration of nanofiltration conditions for separation of alcohol precipitation liquid during preparation of Reduning Injection by Box-Behnken design combined with flux attenuation].

This study employed Box-Behnken design combined with flux attenuation to explore the nanofiltration conditions for separation of alcohol precipitation liquid during the preparation of Reduning Injection and discussed the applicability of nanofiltration in the separation of the liquid with high-concentration ethanol. The effects of nanofiltration molecular weight cut-off(MWCO) and pH on the rejection of chlorogenic acid, 3,5-dicaffeoylquinic acid, and 4,5-dicaffeoylquinic acid were consistent with the principles of pore size sieving and charge effect, respectively. The rejection of the three phenolic acids was reduced by concentration polarization effect caused by trans-membrane pressure(TMP). The swelling of membrane surface decreased the pore size and membrane flux for effective separation. Chlorogenic acid and 4,5-dicaffeoylquinic acid were more sensitive to pH and ethanol concentration than 3,5-dicaffeoylquinic acid. A certain correlation existed between the compound structure and the separation factors of nanofiltration, and the separation rules were associated with the comprehensive effect of charge effect, pore size sieving, concentration polarization, steric hindrance and so on.

Efficacy and Safety of Oral Herbal Drugs Used as Adjunctive Therapy for Melasma: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

BACKGROUND: Melasma is an acquired disorder of facial pigmentation. Its etiology is multifactorial; thus, the management is usually challenging. As a complementary therapy, herbal drugs are often used in the management of melasma. This work was aimed to investigate the efficacy and safety of herbal drugs on melasma in female patients. METHODS: This study followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search was conducted, and all randomised controlled trials (RCTs) on the use of oral herbal drugs as complementary therapy for melasma in female patients were included. A meta-analysis was conducted according to the guidelines of the Cochrane Collaboration using Review Manager 5.4. RESULTS: Ten eligible trials, with 1015 female melasma patients, were included. All of the included RCTs had some concerns for risk of bias for different reasons, especially for that most of included trials were unblinded. Pooled data suggested phytotherapy plus routine therapy had significantly better efficacy on melasma than routine therapy, in terms of response rate (OR: 4.49, 95% CI: 3.25 to 6.20, p < 0.00001), reduction of skin lesion score (SMD: -0.56, 95% CI: -0.79 to -0.33, p < 0.00001), and improvement of serum E2 levels (SMD: -1.58, 95% CI: -2.62 to -0.55, p 0.003). In addition, there was no significant difference in the incidence of AEs between phytotherapy plus routine therapy and routine therapy (OR: 0.92, 95% CI: 0.53 to 1.58; p 0.76). Overall, herbal drugs used as an adjunct to routine therapy significantly enhanced the efficacy for the treatment of melasma but with a comparable safety profile. CONCLUSION: These findings have implications for recommending herbal drugs as a viable complementary treatment option for melasma.

Vitamin D supplementation for the treatment of migraine: A meta-analysis of randomized controlled studies.

INTRODUCTION: It is not well established to use vitamin D supplementation for migraine, and this meta-analysis aims to explore the efficacy of vitamin D for migraine patients. METHODS: PubMed, EMbase, Web of science, EBSCO and Cochrane library databases were systematically searched up to May 2021, and we included randomized controlled trials (RCTs) exploring the effect of vitamin D for migraine patients. RESULTS: Six RCTs and 301 patients were included in the meta-analysis. Compared with control group in migraine patients, vitamin D supplementation could remarkably decrease headache attacks per month (MD = -2.74; 95% CI = -3.82 to -1.67; P < 0.00001), headache days per month (MD = -1.56; 95% CI = -2.44 to -0.68; P = 0.0005) and MIDAS score (MD = -5.72; 95% CI = -10.90 to -0.54; P = 0.03), but demonstrated no obvious influence on attack duration (MD = -2.20; 95% CI = -7.38 to 2.97; P = 0.40) or headache severity (MD = -0.56; 95% CI = -1.18 to 0.06; P = 0.08). CONCLUSIONS: Vitamin D supplementation provided additional benefits to treat migraine.

[Preliminary experimental study on the influence of different tidal volume and frequency of normal minute ventilation on the dynamic changes of carotid blood oxygen in living goats].

Objective: On the basis of preliminarily verifying the use of ultra-fast reaction polymer matrix optical fiber oxygen sensor and its measuring system to record the continuous and dynamic changes of carotid artery oxygen partial pressure (PaO2), in order to analyze and discuss the influence of lung ventilation on the continuous and dynamic changes of PaO2, we designed a whole animal experimental study in vivo. Methods: Four hybrid goats were selected, and the skin was cut and exposed directly under general anesthesia and tracheal intubation. The oxygen sensor, connected with the measuring system, was inserted directly into the left carotid artery to continuously record the dynamic changes of PaO2. With normal minute ventilation,mechanical ventilation is implemented through three tidal volumes: normal tidal volume (VT=15 ml/kg, Rf=20 bpm), half tidal volume (halved VT, doubled Rf) and double tidal volume (doubled VT, halved Rf). Each tidal volume was stable for 10~15 min respectively. We analyzed and calculated the average values of PaO2, the fluctuation magnitudes of PaO2 changes between breaths of last 180 s and the delay times of lung-carotid artery were. We analyzed the effects of different tidal volumes. Results: The heart rate and blood pressure of living goats were maintained stable during the mechanical ventilation experiment with normal ventilation volume Lung-carotid artery delay time is 1.4~1.8 s (about 3 heartbeats at this time). Under normal tidal volume of mechanical ventilation, the average value of PaO2 was (102.94±2.40, 99.38~106.16) mmHg, and the fluctuation range was (21.43±1.65, 19.21~23.59) mmHg, accounting for (20.80± 1.34, 18.65~22.22)% of the average value. Under the condition of halving tidal volume, the average value of PaO2 was maintained at (101.01±4.25, 94.09~105.66) mmHg, which was slightly decreased but not significant (P>0.05 compared with normal mechanical ventilation), but the fluctuation range of PaO2 was significantly reduced to (18.14±1.43, 16.46~20.05) mmHg, accounting for 17.5% of the average value. Under double tidal volume mechanical ventilation, although the average value of PaO2 increased slightly remained at (106.42±4.74, 101.19~114.08) mmHg (P>0.05 compared with normal mechanical ventilation and P<0.05 compared with half tidal volume mechanical ventilation), the fluctuation magnitude of PaO2 increased significantly to (26.58±1.88, 23.46~28.46)mmHg. Conclusion: Inspiration and expiration of normal lung ventilation are the initial factors for the increase and decrease of PaO2 in carotid artery. Under normal ventilation, halving tidal volume and doubling tidal volume significantly changed the fluctuation magnitude of PaO2, but the average value of PaO2 changed only slightly, while the lung-carotid delay time was similar.

[Ultra-fast response polymer optical fiber oxygen measurement device and its preliminary experimental report on continuous dynamic change of arterial oxygen partial pressure under mechanical ventilation in living animals].

Objective: We tried to implant the ultra-fast polymer optical fiber chemical oxygen sensor （POFCOS） into arterial blood vessel,connect with photoelectric conversion measurement system to record the continuous dynamic rapid changes of arterial PO2(PaO2) in whole living animals. It should be the experimental evidence for the new theory of holistic integrative physiology and medicine(HIPM) forexplain the mechanism of respiratory control and regulation in whole circusof respiration-circulation-metabolism. Methods: ①Fabrication of ultrafast POFCOS, calibration and its measuring system: The distal part of 2 m optical fiber was heated and pulled until it became a tapered tip. After cleaning and drying, the tip of 1 mm tapered optical fiber was dip-coated into the luminophore doped polymer solution, then was slowly pumped out while solvent was quickly evaporated to form an oxygen sensing tip, which was dried at room temperature for 24 hours. ②Animal experiments: Under general anesthesia and intubation, goatwas mechanically ventilated with 40%~60% oxygen. We exposed both right and left carotid arteries and the left femoral artery by skin cutting, and inserted the POFCOS directly into the arteries via indwelling catheter. The end of POFCOS were connected to the personal computer through optical fiber, excitation and detection Y-type optical fiber coupler through photoelectric conversion, so as we can realize the continuous dynamic response of living goat carotid PaO2 under mechanical ventilation. We mainly analyzed the intra-breath wave-form alternate increase and decrease of PaO2 and their time delay between lung and carotid arteries.We completes breathing control whole loop to explain the mechanism of mutual breathing and the switching of inspiration and exhalation. Results: The POFCOS has a very fast T90 response time was set 100 ms for liquid. When the heart rate of 40%~60% oxygen mechanical ventilated living goat was ~110 bpm, the PaO2 of left and right carotid artery showed a same wave-sizeup and down following with the inspiration and expiration of ventilator, with a range of up to 15 mmHg. There weresignificant noises of PaO2 change recorded in the left femoral artery. The lung-carotid artery time delay is 1.5~1.7 s after inhalation and exhalation, PaO2 at both left and right carotid arteries starts toincrease and decrease. After two-three heartbeats after the start of lung ventilation, thealternate up-down wave-form information of the arterialized pulmonary vein blood after pulmonary capillaries waspumpedby left ventricle to the position of peripheral chemoreceptors,thus realizing the whole cycle of inhalation and exhalation. It alternately interrupted inhalation, i.e. switching inhalation to exhalation, and then interrupted exhalation,i.e. switching exhalation to inhalation. Conclusion: The ultra-fast reactive implantableoxygen sensor and its measuring system can measure the physiological waveform changes of PaO2 in living animals, which can provide experimental evidence for explaining the mechanism of switching of inspiration-expiration in HIPM.

A-Lipoic Acid Alleviates Folic Acid-Induced Renal Damage Through Inhibition of Ferroptosis.

Folic acid (FA)-induced acute kidney injury (AKI) is characterized by the disturbance of redox homeostasis, resulting in massive tubular necrosis and inflammation. Α-lipoic acid (LA), as an antioxidant, has been reported to play an important role in renal protection, but the underlying mechanism remains poorly explored. The aim of this study is to investigate the protective effect of LA on FA-induced renal damage. Our findings showed that LA could ameliorate renal dysfunction and histopathologic damage induced by FA overdose injection. Moreover, FA injection induced severe inflammation, indicated by increased release of pro-inflammatory cytokines tumor necrosis factor (TNF)-α and IL-1ß, as well as infiltration of macrophage, which can be alleviated by LA supplementation. In addition, LA not only reduced the cellular iron overload by upregulating the expressions of Ferritin and ferroportin (FPN), but also mitigated reactive oxygen species (ROS) accumulation and lipid peroxidation by increasing the levels of antioxidant glutathione (GSH) and glutathione peroxidase-4 (GPX4). More importantly, we found that LA supplementation could reduce the number of Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive tubular cells caused by FA, indicating that the tubular cell death mediated by ferroptosis may be inhibited. Further study demonstrated that LA supplementation could reverse the decreased expression of cystine/glutamate antiporter xCT (SLC7A11), which mediated GSH synthesis. What is more, mechanistic study indicated that p53 activation was involved in the inhibitory effect of SLC7A11 induced by FA administration, which could be suppressed by LA supplementation. Taken together, our findings indicated that LA played the protective effect on FA-induced renal damage mainly by inhibiting ferroptosis.

[Clinical study on the characteristics of exercise pathophysiological in patients with severe heart failure].

Objective: The cardiopulmonary function of patients with chronic heart failure (CHF) was severely limited, but the holistic integrative exercise pathophysiology is still unclear. Methods: After signed the consent form, Eighty three patients with severe CHF from October 2016 to October 2017 in Fuwai Hospital were performed Ramp incremental loading program CardioPulmonary Exercise Testing (CPET), and 12 normal subjects served as control. CPET were performed according to standard of Harbor-UCLA MC and the circulatory, respiratory and metabolic parameters during CPET were measured and analyzed. Results: Peak oxygen uptake (Peak VO2) in CHF (14.33±2.69) ml/(min·kg), (44.25±14.74)%pred was significantly lower than control ((29.42±5.46) ml/(min·kg), (83.88±6.28)%pred). Other core parameters of CPET such as anaerobic threshold (AT), peak oxygen pulse, oxygen uptake efficiency platform (OUEP), the lowest of carbon dioxide output ventilation ratio (Lowest VE/VCO2), and carbon dioxide output ventilation slope (VE/VCO2 Slope) in CHF were significantly different with the control group(P<0.01). The core parameters of lung function, such as forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), FEV1/FVC, and carbon monoxide diffusion (DLCO) were significantly decreased (P<0.01). Systolic blood pressure during all stages of CPET in CHF was significantly lower than control group (P<0.05); Heart rate at AT, peak and recovery stages were significantly lower than control (P<0.01). Minute ventilation, tidal volume and respiratory frequency at rest, warm-up were significantly higher than control (P<0.05). Tidal volume at recovery was significantly higher than control (P<0.05). VO2 at AT, peak and recovery stages in CHF were significantly higher than control (P<0.01). Oxygen pulse at AT and peak were significantly higher than control (P<0.01). Pulse oxygen saturation during all stages of CPET in CHF were significantly lower than control (P<0.01). Conclusion: The decreased holistic functional capacity of cardiogenic CHF dominantly due to circulatory limitation, and secondly due to respiratory and metabolic limitation.

PGE2-JNK signaling axis non-canonically promotes Gli activation by protecting Gli2 from ubiquitin-proteasomal degradation.

Both bench and bedside investigations have challenged the supportive role of Hedgehog (Hh) activity in the progression of colorectal cancers, thus raising a critical need to further deeply determine the contribution of Hh to the growth of colorectal cancer. Combining multiple complementary means, including in vitro and in vivo inflammatory colorectal cancer models, and pathological analysis of clinical colorectal cancer patients samples. We report that colorectal cancer cells hijack prostaglandin E2 (PGE2) to non-canonically promote Hh transcriptional factor Gli activity and Gli-dependent proliferation of colorectal cancer cells in a Smo-independent manner. Mechanistically, PGE2 activates c-Jun N-terminal kinase (JNK), which in turn enables Gli2 to evade ubiquitin-proteasomal degradation by phosphorylating Gli2 at Thr1546. This study not only presents evidence for understanding the contribution of Hh to colorectal cancers, but also provides a novel molecular portrait underlying how PGE2-activated JNK fine-tunes the evasion of Gli2 from ubiquitin-proteasomal degradation. Therefore, it proposes a rationale for the future evaluation of chemopreventive and selective therapeutic strategies for colorectal cancers by targeting PGE2-JNK-Gli signaling route.

Cascade targeting tumor mitochondria with CuS nanoparticles for enhanced photothermal therapy in the second near-infrared window.

Photothermal therapy, assisted by local heat generation using photothermal nanoparticles (NPs), is an emerging strategy to treat tumors noninvasively. To improve treatment outcomes and to alleviate potential side effects on normal tissue cells, utilizing the optically transparent second near-infrared (NIR-II) window and actively targeting tumors are critical. Considering that mitochondria are heat sensitive and play an important role in the up-regulation of metabolic activity in tumor cells, herein we report a cascade targeting scheme that enables active photothermal ablation of tumor mitochondria. First, NIR-II absorbing CuS NPs were surface modified with the mitochondria targeting moiety (3-carboxypropyl) triphenylphosphonium bromide (TPP) and then shielded with CD44 targeting hyaluronic acid, which will only expose TPP upon reaching the tumor sites. This allowed over 90% CuS NP enrichment at tumor mitochondria, and as a result, significantly improved tumor cell photothermal ablation was observed at the cellular level. An in vivo study demonstrated enhanced tumor uptake and improved tumor growth suppression by using these cascade targeting CuS NPs as NIR-II photothermal agents.

Superior hypoglycemic activity of mulberry lacking monosaccharides is accompanied by better activation of the PI3K/Akt and AMPK signaling pathways.

Mulberry has been used as a functional food to treat type 2 diabetes mellitus (T2DM). However, it contains relatively high levels of fructose and glucose, which are not suitable for excess consumption by diabetic patients. In this study we used microbial fermentation to remove fructose and glucose from mulberry fruit, and then determined the effects on glycemia, the phosphatidylinositol 3-hydroxykinase/Akt (PI3K/Akt) and adenosine monophosphate-activated protein kinase (AMPK) signaling pathways and their downstream effectors in T2DM mice. After 5 weeks of administration, fermented mulberry (FM) significantly reduced fasting blood glucose, and also improved insulin sensitivity and glucose tolerance, more effectively than unfermented mulberry (MP). Moreover, compared with MP, FM had a more marked effect on the protein expression of intermediates in the PI3K/Akt and AMPK signaling pathways and their effectors: insulin receptor, phosphorylated Akt (Ser 308), phosphorylated glycogen synthase kinase-3ß (Ser 9), glycogen synthetase, phosphorylated forkhead transcription factor 1 (Ser 256), pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1, 6-bisphosphatase, glucose-6-phosphatase, lipoprotein lipase, and phosphorylated AMPK (Thr 172), glucose transporter 4 and pyruvate kinase. These findings indicate that mulberry fruit modified to remove fructose and glucose may be more promising than whole mulberry as a treatment for diabetes.

[Stoichiometry of carbon, nitrogen and phosphorus and their allometric relationship between leaves and fine roots of three functional tree seedlings.] / 3ç§åŠŸèƒ½åž‹æž—æœ¨å¹¼è‹—å¶ç‰‡ä¸Žç»†æ ¹ç¢³æ°®ç£·åŒ–å­¦è®¡é‡ç‰¹å¾åŠå ¶å¼‚é€Ÿå ³ç³».

We analyzed the contents and stoichiometric ratios of carbon (C), nitrogen (N) and phosphorus (P) in leaves and fine roots of Machilus pauhoi (an evergreen broad-leaved species), Cerasus campanulata (a deciduous broad-leaved species) and Fokienia hodginsii (an evergreen coniferous species) to compare the leaf and root stoichiometry and allometric relationship between different functional groups of trees. There were significant difference in the contents and stoichiometry of C, N and P in the leaves and fine roots among different functional groups. C content, C/N and C/P of the leaves and roots were the highest in M. pauhoi. N content and N/P of the leaves and roots were the highest in C. campanulata, whereas P content of the leaves and roots was the highest in F. hodginsii. The allometric relationship of C, N and P contents as well as their stoichiometric ratios between the leaves and fine roots showed significant difference, which was affected by functional difference. The allometric relationship between C/P and N/P with significantly different allometric indexes in leaves in seedlings of those three tree species, while the isometric relationship between the contents of N and P was found in fine roots. There were significant difference in the C, N and P stoichiometry between the leaves and fine roots. The allometric relationship between leaf C content and root P content in M. pauhoi was detected. C and N contents and C/N, N/P in leaves generally had the allometric or isokinetic relationships with C/N, N/P of fine roots. There were allometric relationships between the leaf C content and the root C, N and P contents in F. hodginsii. It was concluded that nutrient allocation between leaves and fine roots of C. campanulata was more strongly coordinated. The investment strategy of P for leaves and fine roots across those three tree species was similar. The results provided scientific reference for accurate nutrient management at seedling stage and efficient cultivation technique.

The transcription factor GATA10 regulates fertility conversion of a two-line hybrid tms5 mutant rice via the modulation of UbL40 expression.

The thermosensitive genic male sterile 5 (tms5) mutation causes thermosensitive genic male sterility in rice (Oryza sativa) through loss of RNase ZS1 function, which influences ubiquitin fusion ribosomal protein L40 (UbL40 ) messenger RNA levels during male development. Here, we used ATAC-seq, combined with analysis of H3K9ac and H3K4me2, to identify changes in accessible chromatin during fertility conversion of the two-line hybrid rice Wuxiang S (WXS) derived from a mutant tms5 allele. Furthermore, RNA-seq and bioinformatic analyses identified specific transcription factors (TFs) in differentially accessible chromatin regions. Among these TFs, only GATA10 targeted UbL40 . Osgata10 knockout mutations, which resulted in low expression of UbL40 and a tendency toward male fertility, confirmed that GATA10 regulated fertility conversion via the modulation of UbL40 . Meanwhile, GATA10 acted as a mediator for interactions with ERF65, which revealed that transcriptional regulation is a complex process involving multiple complexes of TFs, namely TF modules. It appears that the ERF141/MADS7/MADS50/MYB modules affect metabolic processes that control anther and pollen development, especially cell wall formation. Our analysis revealed that these modules directly or indirectly affect metabolic pathway-related genes to coordinate plant growth with proper anther development, and furthermore, that GATA10 regulates fertility conversion via the modulation of UbL40 expression.

[Effect of "Tongyuan" acupuncture treatment on success rate of extubation in stroke patients undergoing tracheotomy].

OBJECTIVE: To observe the impact of "Tongyuan" (regulating the Governor Vessel to tranquilize mental activities, conducting qi back to its origin) acupuncture treatment on cough reflex, pulmonary infection and swallowing function in stroke patients undergoing tracheotomy. METHODS: Seventy-four cerebral stroke patients with tracheo-tomy were randomly allocated to scalp acupuncture and "Tongyuan" acupuncture groups (n=37 in each group). All the patients of the two groups received basic treatment, including treatment of primary diseases, routine nursing, respiratory muscle training, physical therapy, acupuncture of Chize (LU5), Quchi (LI11), Hegu (LI4), Weizhong (BL40), Zusanli (ST36). In addition, for patients of the scalp acupuncture group, the middle 2/5 of Dingnieqianxiexian (MS6), the middle 2/5 of Dingniehouxiexian (MS7) and Dingpangerxian (MS9) on the contralateral side of lesions were punctured with filiform needles. For patients of the "Tongyuan" acupuncture group, Baihui (GV20), Zhongwan (GV12), Guanyuan (CV4), Qihai (CV6), Tianshu (ST25), Feishu (BL13), Pishu (BL20) were needled. The treatment in both groups lasted 30 minutes each time, once daily, 6 times a week for 4 weeks. The cough reflex grading score (CRGS, assessed according to cough, independent expectoration, sputum suction), clinical pulmonary infection score (CPIS, assessed according to the body temperature, white blood cell count, airway secretion in 24 h, PaO2/FiO2, infiltration status, cultured pathogenic bacteria), and swallowing function were evaluated by a researcher who was blinded to the grouping and treatment procedures. The success rate of extubation was calculated in a week at the end of treatments. RESULTS: After the treatment, the CRGS and CPIS of both groups were apparently decreased in comparison with their own pre-treatment (P<0.05), suggesting an improvement of the cough reflex and pulmonary infection. Regarding the swallowing function, of the two 37 cases in the scalp acupuncture and "Tongyuan" acupuncture groups, 9(24.3%) and 19(51.4%) experienced marked improvement, 12(32.5%)and 14(37.8%) were effective, and 16(43.2%) and 4(10.8%)failed in the treatment, with the effective rate being 56.8% and 89.2%, respectively. In regard to the successful extubation, of the two 37 cases in the scalp acupuncture and "Tongyuan" acupuncture groups, 5(13.5%) and 11(29.8%)had a marked improvement, 10(27.0%)and 18(48.6%)were effective, and 22(59.5%)and 8(21.6%)failed, with the effective rate being 40.5% and 78.4%, respectively. The therapeutic effect of "Tongyuan" acupuncture was significantly superior to that of scalp acupuncture in decreasing CRGS and CPIS, and in improving the swallowing function and raising the rate of successful extubation (P<0.05). CONCLUSION: "Tongyuan" acupuncture treatment can improve cough reflex to remove sputum, reduce pulmonary infection, enhance swallowing function, and raise the success rate of extubation in stroke patients, which is better than scalp acupuncture.

Circular RNA profiling of the rice photo-thermosensitive genic male sterile line Wuxiang S reveals circRNA involved in the fertility transition.

BACKGROUND: Circular RNAs (circRNAs) are known to play an important role in the regulation of gene expression in eukaryotes. Photo-thermosensitive genic male sterile (PTGMS) is a very important germplasm resource in two-line hybrid rice breeding. Although many circRNAs have been identified in rice (Oryza sativa L.), little is known about the biological roles of circRNAs in the fertility transition of the PTGMS rice line. RESULTS: In the present study, RNA-sequencing libraries were constructed from the young panicles of the Wuxiang S sterile line rice (WXS (S)) and its fertile line rice (WXS (F)) at three development stages with three biological replicates. A total of 9994 circRNAs were obtained in WXS rice based on high-throughput strand-specific RNA sequencing and bioinformatic approaches, of which 5305 were known circRNAs and 4689 were novel in rice. And 14 of 16 randomly selected circRNAs were experimentally validated with divergent primers. Our results showed that 186 circRNAs were significantly differentially expressed in WXS (F) compared with WXS (S), of which 97, 87 and 60 circRNAs were differentially expressed at the pollen mother cell (PMC) formation stage (P2), the meiosis stage (P3) and the microspore formation stage (P4), respectively. Fertility specific expression patterns of eight circRNAs were analysis by qRT-PCR. Gene ontology (GO) and KEGG pathway analysis of the parental genes of differentially expressed circRNAs (DECs) revealed that they mainly participated in various biological processes such as development, response to stimulation, hormonal regulation, and reproduction. Furthermore, 15 DECs were found to act as putative miRNA sponges to involved in fertility transition in PTGMS rice line. CONCLUSION: In the present study, the abundance and characteristics of circRNAs were investigated in the PTGMS rice line using bioinformatic approaches. Moreover, the expression patterns of circRNAs were different between WXS (F) and WXS (S). Our findings primarily revealed that circRNAs might be endogenous noncoding regulators of flower and pollen development, and were involved in the fertility transition in the PTGMS rice line, and guide the production and application of two-line hybrid rice.