Preparation, characterization, and liver targeting evaluation of a novel sustained-release brucine self-assembled micelle mediated by glycyrrhetinic acid.

Background: Cancer is a serious threat to human life, health and social development. In recent years, nanomicelles, as an emerging drug carrier material, have gradually entered people's field of vision because of their advantages of improving bioavailability, maintaining drug levels, reducing systemic side effects and increasing drug accumulation at target sites. Methods: In this study, B-GPSG nano-micelles were prepared by film dispersion hydration method using brucine as model drug and glycyrrhetinic acid-polyethylene glycol-3-methylene glycol-dithiodipropionic acid-glycerol monostearate polymer as nano-carrier. The preparation process, characterization, drug release in vitro, pharmacokinetics and liver targeting were investigated. Results: The results showed that the range of particle size, polydispersion index and Zeta potential were 102.7 ± 1.09 nm, 0.201 ± 0.02 and -24.5 ± 0.19 mV respectively. The entrapment efficiency and drug loading were 83.79 ± 2.13% and 12.56 ± 0.09%, respectively. The drug release experiments in vitro and pharmacokinetic experiments showed that it had obvious sustained release effect. For pharmacokinetics study, it shows that both the B-GPSG solution group and the B-PSG solution group changed the metabolic kinetic parameters of brucine, but the B-GPSG solution group had a better effect. Compared with the B-PSG solution group, the drug was more prolonged in rats. The half-life in the body and the retention time in the body of B-GPSG are more helpful to improve the bioavailability of the drug and play a long-term effect. The tail vein injection results of mice indicate that B-GPSG can target and accumulate brucine in the liver without affecting other key organs. Cell uptake experiments and tissue distribution experiments in vivo show that glycyrrhetinic acid modified nano-micelles can increase the accumulation of brucine in hepatocytes, has a good liver targeting effect, and can be used as a new preparation for the treatment of liver cancer. Conclusion: The B-SPSG prepared in this experiment can provide a new treatment method and research idea for the treatment of liver cancer.

Sophoraflavanone G: A review of the phytochemistry and pharmacology.

Bioactive compounds derived from natural sources have long been investigated for the prevention and treatment of human diseases. Sophoraflavanone G (SFG), a lavandulyl flavanone naturally occurring in several Sophora plant species, belongs to the group of prenylated flavonoids that have garnered significant interest in contemporary research. The natural molecule exhibits a wide range of pharmacological properties and shows remarkable efficacy. Its ability to effectively suppress a range of malignant tumor cells, such as leukemia, breast cancer, and lung cancer, is attributed to its multi-target, multi-pathway, and multi-faceted mechanisms of action. Simultaneously, it can also alleviate various inflammatory diseases by mediating inflammatory mediators and molecular pathways. Furthermore, it has the capability to combat antibiotic resistance, exhibit synergistic antibacterial properties with diverse antibiotics, and prevent and treat various agricultural pests. Theoretically, it can bring benefits to human health and has potential value as a drug. Nevertheless, the drawbacks of poor water solubility and inadequate targeting cannot be overlooked. To comprehensively assess the current research on SFG, leverage its structural advantages and pharmacological activity, overcome its low bioavailability limitations, expedite its progression into a novel therapeutic drug, and better serve the clinic, this article presents a overall retrospect of the current research status of SFG. The discussion includes an analysis of the structural characteristics, physicochemical properties, bioavailability, pharmacological activities, and structure-activity relationships of SFG, with the goal of offering valuable insights and guidance for future research endeavors in this field.

Mendelian randomization analysis identified tumor necrosis factor as being associated with severe COVID-19.

Background: Observational studies have shown that anti-tumor necrosis factor (TNF) therapy may be beneficial for patients with coronavirus disease 2019 (COVID-19). Nevertheless, because of the methodological restrictions of traditional observational studies, it is a challenge to make causal inferences. This study involved a two-sample Mendelian randomization analysis to investigate the causal link between nine TNFs and COVID-19 severity using publicly released genome-wide association study summary statistics. Methods: Summary statistics for nine TNFs (21,758 cases) were obtained from a large-scale genome-wide association study. Correlation data between single-nucleotide polymorphisms and severe COVID-19 (18,152 cases vs. 1,145,546 controls) were collected from the COVID-19 host genetics initiative. The causal estimate was calculated by inverse variance-weighted (IVW), MR-Egger, and weighted median methods. Sensitivity tests were conducted to assess the validity of the causal relationship. Results: Genetically predicted TNF receptor superfamily member 6 (FAS) positively correlated with the severity of COVID-19 (IVW, odds ratio = 1.10, 95% confidence interval = 1.01-1.19, p = 0.026), whereas TNF receptor superfamily member 5 (CD40) was protective against severe COVID-19 (IVW, odds ratio = 0.92, 95% confidence interval = 0.87-0.97, p = 0.002). Conclusion: Genetic evidence from this study supports that the increased expression of FAS is associated with the risk of severe COVID-19 and that CD40 may have a potential protective effect against COVID-19.

Stabilizing Supersaturation with Extreme Grain Refinement in Spinodal Aluminum Alloys.

Supersaturated solid solutions can be formed in alloys from various non-equilibrium processes, but stabilizing the metastable phases against decomposition is challenging, particularly the spinodal decomposition that occurs via chemical fluctuations without energy barriers to nucleation. In this work, it is found that spinodal decomposition in supersaturated Al(Zn) solid solutions can be inhibited with straining-induced extreme grain refinement. For the refined supersaturated grains at the nanoscale, their spinodal decomposition is obviously resisted by the relaxed grain boundaries and reduced lattice defects. As grains are refined below 10 nm the decomposition is completely inhibited, in which atomic diffusion is blocked by the stable Schwarz crystal structure with vacancy-free grains. Extreme grain refinement offers a general approach to stabilize supersaturated phases with broadened compositional windows for property modulation of alloys.

Anti-inflammatory effect and antihepatoma mechanism of carrimycin.

BACKGROUND: New drugs are urgently needed for the treatment of liver cancer, a feat that could be feasibly accomplished by finding new therapeutic purposes for marketed drugs to save time and costs. As a new class of national anti-infective drugs, carrimycin (CAM) has strong activity against gram-positive bacteria and no cross resistance with similar drugs. Studies have shown that the components of CAM have anticancer effects. AIM: To obtain a deeper understanding of CAM, its distribution, metabolism and anti-inflammatory effects were assessed in the organs of mice, and its mechanism of action against liver cancer was predicted by a network pharmacology method. METHODS: In this paper, the content of isovaleryl spiramycin III was used as an index to assess the distribution and metabolism of CAM and its effect on inflammatory factors in various mouse tissues and organs. Reverse molecular docking technology was utilized to determine the target of CAM, identify each target protein based on disease type, and establish a target protein-disease type network to ascertain the effect of CAM in liver cancer. Then, the key action targets of CAM in liver cancer were screened by a network pharmacology method, and the core targets were verified by molecular docking and visual analyses. RESULTS: The maximum CAM concentration was reached in the liver, kidney, lung and spleen 2.5 h after intragastric administration. In the intestine, the maximum drug concentration was reached 0.5 h after administration. In addition, CAM significantly reduced the interleukin-4 (IL-4) levels in the lung and kidney and especially the liver and spleen; moreover, CAM significantly reduced the IL-1ß levels in the spleen, liver, and kidney and particularly the small intestine and lung. CAM is predicted to regulate related pathways by acting on many targets, such as albumin, estrogen receptor 1, epidermal growth factor receptor and caspase 3, to treat cancer, inflammation and other diseases. CONCLUSION: We determined that CAM inhibited inflammation. We also predicted the complex multitargeted effects of CAM that involve multiple pathways and the diversity of these effects in the treatment of liver cancer, which provides a basis and direction for further clinical research.

In vivo evaluation and mechanism prediction of anti-diabetic foot ulcer based on component analysis of Ruyi Jinhuang powder.

BACKGROUND: Diabetes is a metabolic disease with a high complication rate. Diabetic foot ulcers (DFUs) seriously affect the quality of life of patients. A total of 15%-20% of diabetic patients develop DFUs, which heal with difficulty over a long time and can result in amputation and disability. Traditional Chinese medicine has a unique effect in the treatment of skin ulcerative diseases. Ruyi Jinhuang powder (RHP) is one of the classic prescriptions in traditional Chinese medicine and is widely used in clinical practice. AIM: To verify the ability of RHP to promote wound healing by electron microscopy analysis in animal models and hematoxylin-eosin (HE) staining. The effective components of RHP were extracted and identified by gas chromatography-mass spectrometry (GC-MS), and the obtained chemical components were analyzed by network pharmacology methods to predict its therapeutic mechanism. METHODS: Sprague Dawley rats were injected with streptozotocin to establish the DFU model. HE staining was used to observe the wound tissue under an electron microscope. The chemical constituents of RHP were extracted first by supercritical fluid extraction and alcohol extraction, and then, GC-MS and ultra-performance liquid chromatography-MS were used to separately identify the chemical constituents. In addition, the "herb-component-target" link was established through the Traditional Chinese Medicine Systems Pharmacology database to obtain the target information, and the molecular docking of important components and key targets was performed in Discovery Studio software. Cytoscape software was used to visualize and analyze the relationship between the chemical composition, targets and Traditional Chinese Medicine network. RESULTS: RHP promoted DFU healing in rats by affecting fibroblasts and nerve cells. A total of 89 chemical components were obtained by GC-MS. Network pharmacological analysis revealed that RHP was associated with 36 targets and 27 pathways in the treatment of DFU, of which the important components were luteolin, trans caryophyllene, ar-turmerone, palmitic acid, methyl palmitate, gallic acid, demethoxycurcumin, berberine, and rheic acid. The key targets were posttranscriptional silencing, topoisomerase II alpha, muscarinic acetylcholine receptor M2, interleukin 6, tumor necrosis factor and retinoic X receptor alpha, and the key pathways were the phosphoinositide 3-kinase-protein kinase B signaling pathway, neuroactive ligand-receptor interactions, and the forkhead box O signaling pathway. CONCLUSION: Our results indicated that RHP may play a role in the treatment of DFU through these target pathways by affecting insulin resistance, altering the nervous system and immune system, participating in inflammatory responses and regulating cell proliferation, differentiation and apoptosis through other specific mechanisms.

Low Dose of Methylprednisolone for Pain and Immune Function After Thoracic Surgery.

BACKGROUND: This study evaluated the effects of single low-dose preoperative methylprednisolone (MP) on the immunologic function and postoperative pain of patients undergoing elective video-assisted thoracoscopic surgery under general anesthesia. METHODS: The study randomly assigned 81 patients who underwent elective video-assisted thoracoscopic surgery to the MP group or the control group. The T-lymphocyte subsets of CD3+, CD4+, and CD8+, and the CD4+/CD8+ ratio at T0 (before anesthesia), T1 (after operation), and T2 (24 hours after operation) were recorded. Also recorded were postoperative rest and cough pain scores and postoperative adverse effects and surgery complications. RESULTS: Compared with T0, the levels of CD3+ and CD4+ subsets and CD4+/CD8+ were significantly decreased, and the level of CD8+ was increased after surgery in both groups. There was no significant difference in the variation of CD3+, CD4+, CD8+, and CD4+/CD8+ between the MP group and the control group. The rest and cough pain of patients in the MP group was significantly lower compared with the control group at 2, 4, 6, and 24 hours after surgery. The incidences of nausea and vomiting and dizziness were also significantly higher in the control group than those in the MP group. CONCLUSIONS: A preoperative single low dose of MP (1 mg/kg) had no effect on immune function but had effective analgesic effects and could reduce the incidence of dizziness and postoperative nausea and vomiting.

Metal-organic framework IRMOFs coated with a temperature-sensitive gel delivering norcantharidin to treat liver cancer.

BACKGROUND: Norcantharidin (NCTD) is suitable for the treatment of primary liver cancer, especially early and middle primary liver cancer. This compound can reduce tumors and improve immune function. However, the side effects of NCTD have limited its application. There is a marked need to reduce the side effects and increase the efficacy of NCTD. AIM: To develop a nanomaterial carrier, NCTD-loaded metal-organic framework IRMOF-3 coated with a temperature-sensitive gel (NCTD-IRMOF-3-Gel), aiming to improve the anticancer activity of NCTD and reduce the drug dose. METHODS: NCTD-IRMOF-3-Gel was obtained by a coordination reaction. The apparent characteristics and in vitro release of NCTD-IRMOF-3-Gel were investigated. Cell cytotoxicity assays, flow cytometry, and apoptosis experiments in mouse hepatoma (Hepa1-6) cells were used to determine the anti-liver cancer activity of NCTD-IRMOF-3-Gel in in vitro models. RESULTS: The particle size of NCTD-IRMOF-3-Gel was 50-100 nm, and the particle size distribution was uniform. The release curve showed that NCTD-IRMOF-3-Gel had an obvious sustained-release effect. The cytotoxicity assays showed that the free drug NCTD and NCTD-IRMOF-3-Gel treatments markedly inhibited Hepa1-6 cell proliferation, and the inhibition rate increased with increasing drug concentration. By flow cytometry, NCTD-IRMOF-3-Gel was observed to block the Hepa1-6 cell cycle in the S and G2/M phases, and the thermosensitive gel nanoparticles may inhibit cell proliferation by inducing cell cycle arrest. Apoptosis experiments showed that NCTD-IRMOF-3-Gel induced the apoptosis of Hepa1-6 cells. CONCLUSION: Our results indicated that the NCTD-IRMOF-3-Gel may be beneficial for liver cancer disease treatment.

Comparison of Morning and Evening Operation Under General Anesthesia on Intraoperative Anesthetic Requirement, Postoperative Sleep Quality, and Pain: A Randomized Controlled Trial.

OBJECTIVE: Postoperative sleep disorders can cause serious adverse effects on postoperative outcomes. The purpose of our study was to compare the effects of the timing of surgery under general anesthesia on intraoperative anesthetic drug requirements, postoperative sleep quality and pain in patients. MATERIALS AND METHODS: Eighty-four patients who underwent selective laparoscopic abdominal surgeries under general anesthesia were randomly assigned to the Day Group (8:00-12:00) or the Night Group (18:00-22:00). The portable sleep monitor (PSM) was used to determine sleep quality on the night before surgery (Sleep-preop), the first night after surgery (Sleep POD 1), and the third night after surgery (Sleep POD 3). The visual analog scale (VAS) was used to evaluate postoperative pain scores and the Athens Insomnia Scale (AIS) was used for assessing insomnia symptoms. The total dose of general anesthetics required and adverse effects after surgery were also assessed. RESULTS: Compared to Sleep-preop, patients presented with a lower sleep efficiency and a higher AIS score during Sleep POD 1 and Sleep POD 3. Furthermore, the Night Group had a significantly lower proportion of rapid eye movement sleep, stable sleep, and unstable sleep than did the Day Group at Sleep POD 1 and Sleep POD 3. The dosage of propofol and remifentanil required in the Day Group was significantly higher than that in the Night Group. Furthermore, patients in the Day Group had better pain relief, with a lower VAS score at 1, 6, 12, and 24 hours after surgery. The incidences of postoperative nausea and vomiting and dizziness were significantly higher in the Night Group than those in the Day Group. CONCLUSION: Morning operations required a higher dose of anesthetic drugs than did evening operations, which may be related to the circadian rhythm. The degree of postoperative sleep disorders was greater when the operation was performed in the evening than in the morning, which was also associated with increased pain perception and increased incidence of postoperative adverse effects. Thus, our results suggest that patients with hyperalgesia and sleep disorders may benefit from operations performed in the morning.

How to use macrophages to realise the treatment of tumour.

Macrophages (Mø) are immune cells with natural phagocytic ability and play an important role in tumorigenesis, development and metastasis. Mø play a dual role of tumour inhibition and tumour promotion in tumour development due to their two different phenotypes. Mø in the tumour microenvironment have long been referred to as tumour-associated Mø (TAMs). Mø are mainly involved in tumour resistance, cancer metastasis and mediating immunosuppression. Nowadays, Mø and Mø membranes have been widely used in drug delivery systems (DDSs) because of their good biocompatibility, natural phagocytosis and their important role in tumour development. In this review, from the perspective of Mø's role in tumour development, we present strategies and drugs of Mø targeting and focusing on the several types of biomimetic nanoparticles constructed by Mø and Mø membranes in tumour therapy, and discuss the problem of this delivery system in present research and future directions.

[Mechanism of the anthocyanin single component cyanidin-3-O-glucoside inhibiting proliferation and migration of B16-F10 cells].

To study the effects of the anthocyanin single component cyanidin-3-O-glucoside (Cy-3-glu) on the proliferation and migration of mouse melanoma cells and to elucidate the underlying mechanisms, B16-F10 cells were treated with different concentrations of Cy-3-glu. Cell viability was analyzed by a CCK-8 method. Cell migration was determined by the callus scratching technique. Cell cycle was measured by the flow cytometry. The expression levels of genes involved in cell cycle regulation were detected by real-time PCR. Protein expression levels of p-AKT, E-cadherin, N-cadherin and vimentin were analyzed by Western blot. The growth and migration of B16-F10 cells in C57BL/6J mice were monitored by the cryogenically cooled IVIS-imaging system. The results showed that Cy-3-glu significantly inhibited the growth (P < 0.001) and migration (P < 0.01) of B16-F10 cells, and arrested the cell cycle in the S phase. After Cy-3-glu treatment, the expression levels of p-AKT (P < 0.05), N-cadherin and vimentin (P < 0.001) were decreased significantly, and the expression level of E-cadherin was dramatically increased (P < 0.05). The size and weight of tumors and tumor metastasis in mice fed with a diet containing Cy-3-glu were significantly reduced (P < 0.05). In conclusion, Cy-3-glu inhibits proliferation and migration of B16-F10 cells by inhibiting the PI3K/AKT signaling pathway, cell adhesion and migration signals.

The Effect Of Intraoperative Use Of Dexmedetomidine During The Daytime Operation Vs The Nighttime Operation On Postoperative Sleep Quality And Pain Under General Anesthesia.

OBJECTIVES: The aim of our study was to compare the effect of using dexmedetomidine (DEX) during the daytime operation or the nighttime operation under general anesthesia on postoperative sleep quality and pain of patients. METHODS: Seventy-five patients scheduled for elective laparoscopic abdominal surgeries under general anesthesia were randomly assigned to receive operation in the Day Group (8:00-12:00) and the Night Group (18:00-22:00). The Portable Sleep Monitor (PSM) was performed on the following 3 nights: the night before surgery (Sleep 1), the first night after surgery (Sleep 2), and the third night after surgery (Sleep 3). Postoperative pain scores using visual analogue scoring scale, subjective sleep quality using the Athens Insomnia Scale, total dose of general anesthetics and PCA pump press numbers were also recorded. RESULTS: Intraoperative administration of DEX for patients in the Day Group could improve sleep quality with a higher sleep efficiency and a lower AIS subjective sleep quality than patients in the Night Group at Sleep 2 (P < 0.001 and P = 0.001, respectively) and Sleep 3 (P < 0.001, respectively). There were marked lower rapid eye movement (REM) sleep and Stable sleep in the Night Group than that in the Day Group at Sleep 2 (P < 0.001 and P = 0.032, respectively) and Sleep 3 (P < 0.001, respectively). Patients in the Day Group have better pain relief and less PCA pump press numbers than patients in the Night Group. CONCLUSION: Using dexmedetomidine during the daytime operation can better improve postoperative sleep quality and pain than nighttime operation in patients undergoing laparoscopic abdominal surgeries.

Strategy for chemotherapeutic delivery using a nanosized porous metal-organic framework with a central composite design.

BACKGROUND: Enhancing drug delivery is an ongoing endeavor in pharmaceutics, especially when the efficacy of chemotherapy for cancer is concerned. In this study, we prepared and evaluated nanosized HKUST-1 (nanoHKUST-1), nanosized metal-organic drug delivery framework, loaded with 5-fluorouracil (5-FU) for potential use in cancer treatment. MATERIALS AND METHODS: NanoHKUST-1 was prepared by reacting copper (II) acetate [Cu(OAc)2] and benzene-1,3,5-tricarboxylic acid (H3BTC) with benzoic acid (C6H5COOH) at room temperature (23.7°C±2.4°C). A central composite design was used to optimize 5-FU-loaded nanoHKUST-1. Contact time, ethanol concentration, and 5-FU:material ratios were the independent variables, and the entrapment efficiency of 5-FU was the response parameter measured. Powder X-ray diffraction, scanning electron microscopy (SEM), transmission electron microscopy (TEM), and nitrogen adsorption were used to determine the morphology of nanoHKUST-1. In addition, 5-FU release studies were conducted, and the in vitro cytotoxicity was evaluated. RESULTS: Entrapment efficiency and drug loading were 9.96% and 40.22%, respectively, while the small-angle X-ray diffraction patterns confirmed a regular porous structure. The SEM and TEM images of the nanoHKUST-1 confirmed the presence of round particles (diameter: approximately 100 nm) and regular polygon arrays of mesoporous channels of approximately 2-5 nm. The half-maximal lethal concentration (LC50) of the 5-FU-loaded nanoHKUST-1 was approximately 10 µg/mL. CONCLUSION: The results indicated that nanoHKUST-1 is a potential vector worth developing as a cancer chemotherapeutic drug delivery system.

Preparation, in vitro and in vivo evaluation of mPEG-PLGA nanoparticles co-loaded with syringopicroside and hydroxytyrosol.

This study investigated the therapeutic efficiency of monomethoxy polyethylene glycol-poly(lactic-co-glycolic acid) (mPEG-PLGA) co-loaded with syringopicroside and hydroxytyrosol as a drug with effective targeting and loading capacity as well as persistent circulation in vivo. The nanoparticles were prepared using a nanoprecipitation method with mPEG-PLGA as nano-carrier co-loaded with syringopicroside and hydroxytyrosol (SH-NPs). The parameters like in vivo pharmacokinetics, biodistribution in vivo, fluorescence in vivo endomicroscopy, and cellular uptake of SH-NPs were investigated. Results showed that the total encapsulation efficiency was 32.38 ± 2.76 %. Total drug loading was 12.01 ± 0.42 %, particle size was 91.70 ± 2.11 nm, polydispersity index was 0.22 ± 0.01, and zeta potential was -24.5 ± 1.16 mV for the optimized SH-NPs. The nanoparticle morphology was characterized using transmission electron microscopy, which indicated that the particles of SH-NPs were in uniformity within the nanosize range and of spherical core shell morphology. Drug release followed Higuchi kinetics. Compared with syringopicroside and hydroxytyrosol mixture (SH), SH-NPs produced drug concentrations that persisted for a significantly longer time in plasma following second-order kinetics. The nanoparticles moved gradually into the cell, thereby increasing the quantity. ALT, AST, and MDA levels were significantly lower on exposure to SH-NPs than in controls. SH-NPs could inhibit the proliferation of HepG2.2.15 cells and could be taken up by HepG2.2.15 cells. The results confirmed that syringopicroside and hydroxytyrosol can be loaded simultaneously into mPEG-PLGA nanoparticles. Using mPEG-PLGA as nano-carrier, sustained release, high distribution in the liver, and protective effects against hepatic injury were observed in comparison to SH.

Size-dependent magnetic order and giant magnetoresistance in organic titanium-benzene multidecker cluster.

Using density functional theory and non-equilibrium Green's function method, we investigated the magnetic and transport properties of small organic titanium-benzene sandwich clusters TinBzn+1 (n = 1-3). The results show that TiBz2 is nonmagnetic while Ti2Bz3 and Ti3Bz4 are ferromagnetic, and our prediction is in agreement with experimental observation. The double exchange mechanism plays a key role in the ferromagnetism of larger clusters. With Ni as the two electrodes, significant spin-filter efficiency (SFE) and giant magnetoresistance (GMR) were found in the TinBzn+1 molecular junction. These transport properties could be controlled by cluster size, bias voltage or gate voltage. Specially, a sign-reversible GMR effect was observed in the Ti2Bz3 molecular junction. Finally, the microscopic mechanisms of SFE and GMR were suggested.

The magnetic and quantum transport properties of benzene-vanadium-borazine mixed sandwich clusters: a new kind of spin filter.

Using density functional theory and the non-equilibrium Green's function technique, we performed theoretical investigations on the magnetic and quantum transport properties of benzene-vanadium-borazine mixed organic/inorganic ligand sandwich clusters. The calculated results show that these finite sandwich clusters coupled to Ni electrodes exhibit novel quantum transport properties such as half-metallicity, negative differential resistance and spin-reversal effect, and can be viewed as a new kind of spin filter. However, for the infinite molecular wire, the ground state was identified as a ferromagnetic semiconductor with high stability. These findings suggest that the mixed organic/inorganic ligand sandwich clusters and molecular wires are promising materials for application in molecular electronics and spintronics.