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.

[Effect of somatostatin on gastrointestinal hormone levels and clinical outcomes in critically ill infants after gastrointestinal surgery: a prospective randomized controlled study]. / ç”Ÿé•¿æŠ‘ç´ å¯¹é‡ç—‡æ¶ˆåŒ–é“æœ¯åŽå©´å„¿èƒƒè‚ æ¿€ç´ æ°´å¹³å’Œä¸´åºŠé¢„åŽçš„å½±å“ï¼šä¸€é¡¹å‰çž»æ€§éšæœºå¯¹ç §ç ”ç©¶.

OBJECTIVES: To explore the effects of somatostatin on the levels of gastrointestinal hormones and clinical outcomes in critically ill infants after gastrointestinal surgery. METHODS: Using a random number table method, critically ill infants after gastrointestinal surgery who were admitted to the Intensive Care Unit of Xuzhou Children's Hospital from June 2019 to June 2021 were randomly divided into an observation group (29 cases) and a control group (30 cases). The control group received routine treatment such as anti-infection and hemostasis after surgery, while the observation group received somatostatin in addition to the routine treatment [3.5 µg/(kg·h) infusion for 7 days]. The levels of serum gastrin (GAS), motilin (MTL), insulin, and glucagon-like peptide-1 (GLP-1) before surgery, on the 3rd day after surgery, and on the 7th day after surgery were compared between the two groups. The recovery progress and incidence of complications after surgery were also compared between the two groups. RESULTS: There was no significant difference in the levels of serum GAS, MTL, insulin, and GLP-1 between the two groups before surgery (P>0.05). On the 3rd and 7th day after surgery, the levels of serum GAS, MTL, insulin, and GLP-1 in the observation group were higher than those in the control group (P<0.05). In the observation group, the levels of GAS, MTL, insulin, and GLP-1 on the 7th day after surgery were higher than those before surgery and on the 3rd day after surgery (P<0.05), and the levels on the 3rd day after surgery were higher than those before surgery (P<0.05). There was no significant difference in the levels of serum GAS, MTL, and insulin before surgery, on the 3rd day after surgery, and on the 7th day after surgery in the control group (P>0.05). The level of GLP-1 on the 7th day after surgery was higher than that before surgery and on the 3rd day after surgery (P<0.05), and the level on the 3rd day after surgery was higher than that before surgery (P<0.05) in the control group. The observation group had shorter first time of anal exhaust, recovery time of bowel sounds, and first time of defecation after surgery compared to the control group (P<0.05). The incidence of complications after surgery in the observation group was lower than that in the control group (10% vs 33%, P<0.05). CONCLUSIONS: Somatostatin can increase the levels of serum GAS, MTL, insulin, and GLP-1 in critically ill infants after gastrointestinal surgery, promote the recovery of gastrointestinal function, and reduce the incidence of postoperative complications.

Reversal of HMGA1-Mediated Immunosuppression Synergizes with Immunogenic Magnetothermodynamic for Improved Hepatocellular Carcinoma Therapy.

Magnetothermodynamic (MTD) therapy can activate antitumor immune responses by inducing potent immunogenic tumor cell death. However, tumor development is often accompanied by multifarious immunosuppressive mechanisms that can counter the efficacy of immunogenic MTD therapy. High-mobility group protein A1 (HMGA1) is overexpressed within hepatocellular carcinoma tissues and plays a crucial function in the generation of immunosuppressive effects. The reversal of HMGA1-mediated immunosuppression could enhance immunogenic tumor cell death-induced immune responses. A ferrimagnetic vortex-domain iron oxide (FVIO) nanoring-based nanovehicle was developed, which is capable of efficiently mediating an alternating magnetic field for immunogenic tumor cell death induction, while concurrently delivering HMGA1 small interfering (si)RNA (siHMGA1) to the cytoplasm of hepatocellular carcinoma Hepa 1-6 cells for HMGA1 pathway interference. Using siHMGA1-FVIO-mediated MTD therapy, the proliferation of hepatocellular carcinoma Hepa 1-6 tumors was inhibited, and the survival of a mouse model was improved. We also demonstrated that siHMGA1-FVIO-mediated MTD achieved synergistic antitumor effects in a subcutaneous hepatocellular carcinoma Hepa 1-6 and H22 tumor model by promoting dendritic cell maturation, enhancing antigen-presenting molecule expression (both major histocompatibility complexes I and II), improving tumor-infiltrating T lymphocyte numbers, and decreasing immunosuppressive myeloid-derived suppressor cells, interleukin-10, and transforming growth factor-ß expression. The nanoparticle system outlined in this paper has the potential to target HMGA1 and, in combination with MTD-induced immunotherapy, is a promising approach for hepatocellular carcinoma treatment.

Rugby ball-shaped magnetic microcapsule for tumor hyperthermia.

Magnetic hyperthermia (MH) induced by magnetic particles has been widely used to treat tumors. However, the limited heating conversion efficiency inspires the design and synthesis of versatile magnetic materials for enhancing the performance of MH. Herein, we developed rugby ball-shaped magnetic microcapsules as efficient MH agents. The size and shape of the microcapsules can be precisely controlled by adjusting the reaction time and temperature without surfactant assistance. Because of their high saturation magnetization and uniform size/morphology, the microcapsules showed excellent thermal conversion efficiency, with a specific absorption rate of 2391 W g-1. Additionally, we performed in vivo anti-tumor studies on mice and found that MH mediated by magnetic microcapsules effectively inhibited the advancement of hepatocellular carcinoma. The microcapsules' porous structure might allow them to efficiently load different therapeutic drugs and/or functional species. These beneficial properties make microcapsules ideal candidates for medical applications, particularly in disease therapy and tissue engineering.

Engineering magnetic nano-manipulators for boosting cancer immunotherapy.

Cancer immunotherapy has shown promising therapeutic results in the clinic, albeit only in a limited number of cancer types, and its efficacy remains less than satisfactory. Nanoparticle-based approaches have been shown to increase the response to immunotherapies to address this limitation. In particular, magnetic nanoparticles (MNPs) as a powerful manipulator are an appealing option for comprehensively regulating the immune system in vivo due to their unique magnetically responsive properties and high biocompatibility. This review focuses on assessing the potential applications of MNPs in enhancing tumor accumulation of immunotherapeutic agents and immunogenicity, improving immune cell infiltration, and creating an immunotherapy-sensitive environment. We summarize recent progress in the application of MNP-based manipulators to augment the efficacy of immunotherapy, by MNPs and their multiple magnetically responsive effects under different types of external magnetic field. Furthermore, we highlight the mechanisms underlying the promotion of antitumor immunity, including magnetically actuated delivery and controlled release of immunotherapeutic agents, tracking and visualization of immune response in real time, and magnetic regulation of innate/adaptive immune cells. Finally, we consider perspectives and challenges in MNP-based immunotherapy.

[Effect of somatostatin on postoperative gastrointestinal function and stress level in children with acute abdomen: a prospective randomized controlled study]. / ç”Ÿé•¿æŠ‘ç´ å¯¹æ€¥è ¹ç—‡æ‚£å„¿æœ¯åŽèƒƒè‚ åŠŸèƒ½åŠåº”æ¿€æ°´å¹³å½±å“çš„å‰çž»æ€§éšæœºå¯¹ç §ç ”ç©¶.

OBJECTIVES: To study the effect of somatostatin on postoperative gastrointestinal function and stress level in children with acute abdomen. METHODS: A total of 102 children with acute abdomen who underwent surgery in Xuzhou Children's Hospital from August 2019 to June 2021 were enrolled as subjects and were randomly divided into an observation group and a control group, with 51 children in each group. The children in the control group were given conventional treatment such as hemostasis and anti-infective therapy after surgery, and those in the observation group were given somatostatin in addition to conventional treatment. Peripheral blood samples were collected from both groups before surgery and on days 1 and 5 after surgery. The two groups were compared in terms of the serum levels of endothelin-1 (ET-1), adrenocorticotropic hormone (ACTH), cortisol, gastrin, and motilin, postoperative recovery, and the incidence rate of complications. RESULTS: There was no significant difference in the serum levels of ET-1, ACTH, cortisol, gastrin, and motilin between the two groups before surgery (P>0.05). Compared with the control group, the observation group had significantly lower serum levels of ET-1, ACTH, and cortisol on days 1 and 5 after surgery (P<0.05) and significantly higher levels of motilin and gastrin on day 5 after surgery (P<0.05). Compared with the control group, the observation group had significantly shorter time to first passage of flatus, first bowel sounds, and first defecation after surgery, as well as a significantly shorter length of hospital stay (P<0.05). The incidence rate of complications in the observation group was significantly lower than that in the control group (6% vs 24%, P<0.05). CONCLUSIONS: In children with acute abdomen, somatostatin can significantly reduce postoperative stress response, improve gastrointestinal function, and reduce the incidence rate of complications, thereby helping to achieve a good prognosis.

Enhancement of CD8+ T-Cell-Mediated Tumor Immunotherapy via Magnetic Hyperthermia.

Magnetic hyperthermia (MHT) uses magnetic iron oxide nanoparticles (MIONs) to irradiate heat when subjected to an alternating magnetic field (AMF), which then trigger a series of biological effects to realize rapid tumor-killing effects. With the deepening in research, MHT has also shown significant potential in achieving antitumor immunity. On the other hand, immunotherapy in cancer treatment has gained increasing attention over recent years and excellent results have generally been reported. Using MHT to activate antitumor immunity and clarifying its synergistic mechanism, i. e., immunogenic cell death (ICD) and immunosuppressive tumor microenvironment (TME) reversal, can achieve a synergistically enhanced therapeutic effect on primary tumors and metastatic lesions, and this can prevent cancer recurrence and metastasis, which thus prolong survival. In this review, we discussed the role of MHT when utilized alone and combining MHT with other treatments (such as radiotherapy, photodynamic therapy, and immune checkpoint blockers) in the process of tumor immunotherapy, including antigen release, dendritic cells (DCs) maturation, and activation of CD8+ cytotoxic T lymphocytes. Finally, the challenges and future development of current MHT and immunotherapy are discussed.

Coptisine, a protoberberine alkaloid, relaxes mouse airway smooth muscle via blockade of VDLCCs and NSCCs.

BACKGROUND/AIMS: Recently, effective and purified ingredients of traditional Chinese medicine (TCM) were extracted to play crucial roles in the treatment of pulmonary diseases. Our previous research focused on TCM drug screening aimed at abnormal airway muscle contraction during respiratory diseases. Coptisine, an effective ingredient extracted from bitter herbs has shown a series of antioxidant, antibacterial, cardioprotective and neuroprotective pharmacological properties. In the current study, we questioned whether coptisine could also participate in asthma treatment through relaxing abnormal contracted mouse airway smooth muscle (ASM). The present study aimed to characterize the relaxant effects of coptisine on mouse ASM and uncover the underlying molecular mechanisms. METHODS: To investigate the role of coptisine on pre-contracted mouse ASM, a series of biological techniques, including force measurement and patch-clamp experiments were employed. RESULTS: Coptisine was found to inhibit high K+ or acetylcholine chloride (ACh)-induced pre-contracted mouse tracheal rings in a dose-dependent manner. Further research demonstrated that the coptisine-induced mouse ASM relaxation was mediated by alteration of calcium mobilization via voltage-dependent L-type Ca2+ channels (VDLCCs) and non-selective cation channels (NSCCs). CONCLUSION: Our data showed that mouse ASM could be relaxed by coptisine via altering the intracellular Ca2+ concentration through blocking VDLCCs and NSCCs, which suggested that this pharmacological active constituent might be classified as a potential new drug for the treatment of abnormal airway muscle contraction.

Benidipine, an anti-hypertensive drug, relaxes mouse airway smooth muscle.

AIMS: Benidipine is a dihydropyridine (DHP) derived Ca2+ antagonist, can block triple Ca2+ channels (L, N, and T). It has been used as a safety anti-hypertensive drug because of its long-acting relaxant effect on vascular smooth muscle (VSM). However, whether benidipine has similar pharmacological actions in airway smooth muscle (ASM) is unknown. This research aims to reveal the relaxant property and Ca2+ antagonistic effect of benidipine on ASM. MAIN METHODS: The relaxant property of mouse ASM was investigated by tissue tension tests, and Ca2+ antagonistic effect was evaluated through patch-clamp techniques. KEY FINDINGS: Benidipine caused dose-dependent relaxations on high K+ (80 mM) induced precontraction in mouse ASM, which relied on inhibition of extracellular Ca2+ influx, and 1 µM benidipine totally blocked L-type voltage-dependent Ca2+ channels (LVDCCs) currents in airway smooth muscle cells (ASMCs). Benidipine also showed dose-dependent inhibition of ACh-induced precontraction with or without the LVDCCs blocker nifedipine, and 100 µM benidipine blocked ACh-stimulated Ca2+ influx through not only LVDCCs but also non-selective cation channels (NSCCs). SIGNIFICANCE: Benidipine blocked LVDCCs and NSCCs to abolish these channels-mediated Ca2+ influx, which relaxed precontracted ASM. This study represented benidipine with a new potential medicinal value for ASM hypercontractility.

Deficiency of MTMR14 impairs male fertility in Mus musculus.

Calcium signalling is critical for successful fertilization. In spermatozoa, capacitation, hyperactivation of motility and acrosome reactions are all mediated by increases in intracellular Ca2+. Our previous reports have shown that deficiency of MTMR14, a novel phosphoinositide phosphatase, induces a muscle disorder by disrupting Ca2+ homeostasis. Recently, we found that MTMR14 is also expressed in the testes; however, whether deficiency of MTMR14 in the testes also alters the Ca2+ concentration and impairs male fertility remains entirely unknown. In the present study, we found that MTMR14 is also expressed in the testes and mature sperm cells, suggesting that deficiency of MTMR14 might have some effect on male fertility. Both in vivo fertility and in vitro fertilization tests were then performed, and we found that MTMR14-/- male mice showed decreased fertility. A series of experiments were then arranged to test the testis and sperm parameters; we found that MTMR14 deficiency caused small size of the testes, small numbers of both total and immotile sperm, expanded membrane of sperm tail, a decreased proportion of acrosome reaction, and in contrast, an increased proportion of abnormal sperm and augmented apoptosis, etc. Further study also found that the muscle force of the vas deferens decreased significantly in KO mice. Intracellular calcium homeostasis in the testes and epididymis was impaired by MTMR14 deletion; moreover, the relative mRNA expression levels of Itpr1, Itpr2, and Ryr3 were dramatically decreased in MTMR14 KO mice. Thus, MTMR14 deletion impairs male fertility by causing decreased muscle force of the vas deferens and intracellular calcium imbalance.

Effects of maltose and lysine treatment on coffee aroma by flash gas chromatography electronic nose and gas chromatography-mass spectrometry.

BACKGROUND: Arabica coffee is a sub-tropical agricultural product in China. Coffee undergoes a series of thermal reactions to form abundant volatile profiles after roasting, so it loses a lot of reducing sugars and amino acids. Adding carbonyl compounds with amino acids before roasting could ensure the nutrition and flavour of coffee. The technology is versatile for the development of coffee roasting process. This investigation evaluates the effects of combining maltose and lysine (Lys) to modify coffee aroma and the possibly related mechanisms. Arabica coffee was pretreated with a series of solvent ratios of maltose and Lys with an identical concentration (0.25 mol L-1 ) before microwave heating. RESULTS: It was found that the combination of maltose and Lys significantly (P ≤ 0.05) influenced quality indices of coffee (pH and browning degree). Ninety-six aromatic volatiles have been isolated and identified. Twelve volatile profiles revealed the relationship between fragrance difference and compound content in coffee. Moreover, coffee aroma was modified by a large number of volatiles with different chemical classes and character. CONCLUSION: Thus, our results suggest that the combination of reagents changed overall aroma quality through a series of complex thermal reactions, especially the ratio of Lys/maltose over 2:1. © 2017 Society of Chemical Industry.

Chloroform Extract of Artemisia annua L. Relaxes Mouse Airway Smooth Muscle.

Artemisia annua L. belongs to the Asteraceae family, which is indigenous to China. It has valuable pharmacological properties, such as antimalarial, anti-inflammatory, and anticancer properties. However, whether it possesses antiasthma properties is unknown. In the current study, chloroform extract of Artemisia annua L. (CEAA) was prepared, and we found that CEAA completely eliminated acetylcholine (ACh) or high K+-elicited (80 mM) contractions of mouse tracheal rings (TRs). Patch-clamp technique and ion channel blockers were employed to explore the underlying mechanisms of the relaxant effect of CEAA. In whole-cell current recording, CEAA almost fully abolished voltage-dependent Ca2+ channel (VDCC) currents and markedly enhanced large conductance Ca2+-activated K+ (BK) channel currents on airway smooth muscle cells (ASMCs). In single channel current recording, CEAA increased the opening probability but had no effect on the single channel conductance of BK channels. However, under paxilline-preincubated (a selective BK channel blocker) conditions, CEAA only slightly increased BK channel currents. These results indicate that CEAA may contain active components with potent antiasthma activity. The abolished VDCCs by CEAA may mainly contribute to the underlying mechanism through which it acts as an effective antiasthmatic compound, but the enhanced BK currents might play a less important role in the antiasthmatic effects.

Metformin Attenuates Neurological Deficit after Intracerebral Hemorrhage by Inhibiting Apoptosis, Oxidative Stress and Neuroinflammation in Rats.

Intracerebral hemorrhage (ICH) can lead to brain damage and even death, and there is lack of effective therapeutic methods for treating ICH. Although recent studies have focused on the administration of metformin in treating stroke, there is no literature to support whether it can be used to treat ICH. Therefore, the aim of this study was to evaluate the possible effects of metformin on ICH and the underlying mechanisms of those effects. An ICH model was established in adult male Sprague-Dawley rats. Rats were randomly divided into three groups: sham group, ICH group, and ICH+metformin group. The neurobehavioral deficit scoring method was used to examine neurological function in rats. The levels of lipid peroxidation antioxidant enzyme and 8-iso-PGF2α were detected to evaluate oxidative stress. Survival of striatal neurons was examined by TUNEL staining, immunohistochemistry and HE staining. The levels of p-JNK, p-c-Jun and cleaved caspase-3 in the striatum were measured by western blotting. The results demonstrated that metformin protected rats from neurological deficits induced by ICH. Moreover, metformin reduced oxidative stress and preserved the survival of striatal neurons under ICH conditions. Furthermore, metformin downregulated the levels of apoptotic factors (p-JNK3, p-c-Jun and cleaved caspase-3) as well as pro-inflammatory cytokines (IL-1ß, IL-4 and IL-6 and TNF-α). Collectively, we speculate that metformin may be a potential clinical treatment for ICH patients.

Metformin Attenuates Cognitive Impairments in Hypoxia-Ischemia Neonatal Rats via Improving Remyelination.

Perinatal hypoxia-ischemia (H/I) causes brain injury and myelination damage. Finding efficient methods to restore myelination is critical for the recovery of brain impairments. By applying an H/I rat model, we demonstrate that metformin (Met) treatment significantly ameliorates the loss of locomotor activity and cognition of H/I rat in the Morris water maze and open field task tests. After administration of Met to H/I rat, the proliferation of Olig2+ oligodendrocyte progenitor cells and the expression of myelin basic protein are obviously increased in the corpus callosum. Additionally, the myelin sheaths are more compact and the impairments are evidently attenuated. These data indicate that Met is beneficial for the amelioration of H/I-induced myelination and behavior deficits.