Understanding sorafenib-induced ferroptosis and resistance mechanisms: Implications for cancer therapy.

Sorafenib is an important first-line treatment option for liver cancer due to its well-characterized safety profile. While novel first-line drugs may have better efficacy than Sorafenib, they also have limitations such as worse safety and cost-effectiveness. In addition to inducing apoptosis, Sorafenib can also trigger ferroptosis, which has recently been recognized as an immunogenic cell death, unleashing new possibilities for cancer treatment. However, resistance to Sorafenib-induced ferroptosis remains a major challenge. To overcome this resistance and augment the efficacy of Sorafenib, a wide range of nanomedicines has been developed to amplify its pro-ferroptotic effects. This review highlights the mechanisms underlying Sorafenib-triggered ferroptosis and its resistance, and outlines innovative strategies, particularly nanomedicines, to overcome ferroptosis resistance. Moreover, we summarize molecular biomarkers that signify resistance to Sorafenib-mediated ferroptosis, which can assist in predicting therapeutic outcomes.

Improvement, Validation, and Analysis of Colles Fracture Treated with an Integrated Retainer Pad Splint.

Objective: To observe the effectiveness and safety of the Colles fracture treated with the integrated retainer pad splint and to compare the clinical and radiological outcomes of the integrated retainer pad splint and the traditional bamboo curtain splint in the treatment of the Colles fracture. Methods: A total of 100 patients with Colles fractures were randomly divided into two groups: the treatment group was fixed with the integrated retainer pad splint (IS), and the control group was fixed with the traditional bamboo curtain splint (TS).The range of wrist motion was measured at follow-up examinations, and volar inclination, ulnar deviation, and radial height were measured on radiographs. Regular follow-up wrist imaging examinations and functional examinations were performed before reduction, after reduction, and at the 1st, 3rd, 5th, and 8th weeks. The two groups were compared in terms of convenience, fracture healing time, X-ray data of volar inclination, ulnar deviation, radial height, and wrist joint function. The relevant data were analyzed with SPSS 25.0 statistical software. Results: There were no notable differences in gender, age, and injured side between IS and TS groups. In terms of operation time, IS was better than the TS group (P < 0.05), and the operation time in the IS group was shorter. On the basis of X-ray data of volar inclination, ulnar deviation, and radial height measured on radiographs, the difference between the IS and TS groups was statistically significant (P < 0.05), which showed that the IS group was more stable in fracture fixation and had less reduction loss during the treatment process. At the 8th week of treatment, the wrist Gartland-Werley score of the two groups showed that the two fixation methods are equivalent in restoring wrist joint function (P > 0.05); however, in terms of the excellent and good rate of wrist joint function, the IS group scored 96% was higher than the TS group (80%). Conclusion: Compared with the traditional bamboo curtain splint, the integrated retainer pad splint is more convenient and stable, and it has less reduction loss during the treatment. Repair of the Colles fracture using the integrated retainer pad splint with external fixation results in nearly normal return of function, which is significantly better than using the traditional bamboo curtain splint.

Study on the Enhanced Remediation of Petroleum-Contaminated Soil by Biochar/g-C3N4 Composites.

This work developed an environmentally-friendly soil remediation method based on BC and g-C3N4, and demonstrated the technical feasibility of remediating petroleum-contaminated soil with biochar/graphite carbon nitride (BC/g-C3N4). The synthesis of BC/g-C3N4 composites was used for the removal of TPH in soil via adsorption and photocatalysis. BC, g-C3N4, and BC/g-C3N4 have been characterized by scanning electron microscopy (SEM), Brunauer-Emmett-Teller surface area analyzer (BET), FT-IR, and X-ray diffraction (XRD). BC/g-C3N4 facilitates the degradation due to reducing recombination and better electron-hole pair separation. BC, g-C3N4, and BC/g-C3N4 were tested for their adsorption and photocatalytic degradation capacities. Excellent and promising results are brought out by an apparent synergism between adsorption and photocatalysis. The optimum doping ratio of 1:3 between BC and g-C3N4 was determined by single-factor experiments. The removal rate of total petroleum hydrocarbons (TPH) by BC/g-C3N4 reached 54.5% by adding BC/g-C3N4 at a dosing rate of 0.08 g/g in a neutral soil with 10% moisture content, which was 2.12 and 1.95 times of BC and g-C3N4, respectively. The removal process of TPH by BC/g-C3N4 conformed to the pseudo-second-order kinetic model. In addition, the removal rates of different petroleum components in soil were analyzed in terms of gas chromatography-mass spectrometry (GC-MS), and the removal rates of nC13-nC35 were above 90% with the contaminated soil treated by BC/g-C3N4. The radical scavenger experiments indicated that superoxide radical played the major role in the photocatalytic degradation of TPH. This work definitely demonstrates that the BC/g-C3N4 composites have great potential for application in the remediation of organic pollutant contaminated soil.

Tumor-targeted hyaluronic acid-mPEG modified nanostructured lipid carriers for cantharidin delivery: An in vivo and in vitro study.

AIM: Cantharidin (CTD), the major component of the anti-cancer medicine obtained from Mylabris cichorii, exerts good inhibitory effects on several cancers, such as liver and breast cancer. However, owing to its toxicity, its oral administration can cause various adverse effects, limiting its clinical applications. Therefore, the development of a novel nano-drug delivery system for CTD would be highly beneficial. METHODS: A nanostructured lipid carrier (NLC) was designed to actively target CTD to tumor cells using a hyaluronic acid (HA)-decorated copolymer (mPEG-NH2); the NLCs were called HA-mPEG-CTD-NLC. HA-mPEG was synthesized using amidation, and HA-mPEG-CTD-NLC was generated through ultrasonic emulsification in water. The mean hydrodynamic diameter of the particles was approximately 119.3 nm. RESULTS: Pharmacokinetic studies revealed that the half-life of HA-mPEG-CTD-NLC and its area under the curve were higher than those of a CTD solution. Further, the plasma clearance rate of HA-mPEG-CTD-NLC was 0.41 times that of the CTD solution, implying a significantly prolonged drug retention time in vivo. Fluorescence in vivo endo-microscopy and optical in vivo imaging revealed that HA-mPEG-CTD-NLC had superior cytotoxicity and targeting efficacy against SMMC-7721 cells. An evaluation of the in vivo anti-tumor activity showed that HA-mPEG-CTD-NLC significantly inhibited tumor growth and prolonged survival in tumor-bearing mice, with a tumor inhibition rate of 65.96%. CONCLUSIONS: Our results indicate that HA-mPEG-CTD-NLC may have great potential in liver cancer-targeted therapy.

[Detoxification mechanism of Aconiti Lateralis Radix Praeparata combined with dried Rehmanniae Radix based on metabolic enzymes in liver].

The enzymes CYP1 A2 and CYP3 A4 were measured by building a "Cocktail" probe drug and the incubation system of liver microsomes. The compatibility of Aconiti Lateralis Radix Praeparata combined with dried Rehmanniae Radix on CYP450 enzyme protein and gene expression was explored from the level of protein and molecular biology. It explored the molecular mechanism of compatibility detoxication of Aconiti Lateralis Radix Praeparata to provide scientific support for clinical safe and effective application of Aconiti Lateralis Radix Praeparata. The CYP450 enzyme activity was determined by using "Cocktail" probe drugs. The content of CYP450 enzyme was measured by CO reduction of differential spectrum method. The mRNA expression of CYP1 A2 and CYP3 A4 enzyme was detected by RT-PCR technology. Compared with the blank group, the CYP1 A2 and CYP3 A4 enzyme activity and mRNA expression were increased in the dried Rehmanniae Radix combined with Aconiti Lateralis Radix Praeparata group with significant differences(P<0.05), while the CYP3 A4 enzyme activity and mRNA expression were no influence in the Aconiti Lateralis Radix Praeparata group. The CYP3 A4 enzyme activity and mRNA expression were increased in the dried Rehmanniae Radix and the dried Rehmanniae Radix combined with Aconiti Lateralis Radix Praeparata group, and there were significant differences(P<0.05). The content of CYP450 enzyme was decreased in the Aconiti Lateralis Radix Praeparata group, contributed to extremely significant difference(P<0.01). The content of CYP450 enzyme was increased in the dried Rehmanniae Radix and the dried Rehmanniae Radix combined with Aconiti Lateralis Radix Praeparata group, and there were significant differences(P<0.05). The CYP1 A2 and CYP3 A4 enzyme activity and gene expression were enhanced after dried Rehmanniae Radix combined with Aconiti Lateralis Radix Praeparata. The metabolism of toxic ingredients of Aconiti Lateralis Radix Praeparata was accelerated to reach an effect of detoxication. The detoxication mechanism of compatibility of Aconiti Lateralis Radix Praeparata was verified from the viewpoint of liver metabolic enzymes.

Dexamethasone combined with berberine is an effective therapy for bleomycin-induced pulmonary fibrosis in rats.

Pulmonary fibrosis (PF) is a heterogeneous pathological process in lung tissues with a considerable mortality rate. Currently, combination therapy represents an effective approach to treat PF. Dexamethasone (Dxs) and berberine (BBR) are widely applied to inhibit the progression of PF. Dxs plus penehyclidine hydrochloride or alfacalcidol have been reported more effective in therapy compared with any single drug treatment. However, whether Dxs plus BBR induces an increased antifibrotic effect remains unknown. The current study aimed to evaluate the therapeutic effect of BBR plus Dxs in bleomycin (BLM)-induced PF. A PF model in rats was established and rats were divided into control, BLM, BBR, Dxs and BBR plus Dxs groups (n=9/group). On days 3, 7 and 14, blood samples were collected from the eyes of the rats (n=6/group). CXC chemokine ligand 14 (CXCL14), collagen I, collagen III, matrix metalloproteinase (MMP)2 and MMP9 serum levels were measured by ELISA. On day 14, all rats were sacrificed. Hematoxylin and eosin analysis, Masson staining and hydroxyproline (Hyp) assessment were performed to observe histopathological changes and collagen deposition. mRNA and protein levels of CXCL14, CXC chemokine receptor 4 (CXCR4), collagen I/III, α-smooth muscle actin (α-SMA), MMP2/9 and phosphorylated-Smad 2/3 in lung tissue were further evaluated. Similar effects in preventing lung damage were observed histopathologically for Dxs and BBR compared with the BLM group. These treatments further reduced levels of Hyp, CXCL14, CXCR4, collagen I/III, MMP2/9, α-SMA and p-Smad 2/3. The combination of Dxs and BBR exhibited increased effectiveness compared with the single treatments. Results further suggested that antifibrotic mechanisms were involved in inhibiting CXCL14 and MMP2/MMP9 expression, and preventing the activation of Smad2/3 and hedgehog signaling pathways. The combined use of Dxs and BBR may represent a potential therapeutic approach for PF.

Impact of the Herbal Breviscapine on the Pharmacokinetics of Simvastatin in Rats: The Involvement of CYP3A4.

The effect of breviscapine injection on the pharmacokinetics of simvastatin and the mRNA expression of hepatic cytochrome P450 (CYP) enzyme was investigated with rats. The rats were pretreated for 8 consecutive days with breviscapine injection (20 mg/kg/day, i. v.), followed by administration of simvastatin through gavage (40 mg/kg). The control rats received the corresponding volume of saline solution for the pretreatment. Blood samples were collected at varied time points after simvastatin administration and the liver was harvested after the last collection of the blood sample for measurement of the CYP3A4 mRNA expression. Pre-treatment with breviscapine injection led to increased plasma concentration of simvastatin, showing 57% increase for AUC0-∞ (P<0.01), 31% increase for C max (P<0.01), and 36% decrease for the total plasma clearance, compared with the control. Pre-treatment with breviscapine injection also inhibited the mRNA expression of the hepatic CYP3A4. These findings indicate that pre-treatment with breviscapine injection could increase the plasma concentration of simvastatin, possibly by inhibiting the expression of the hepatic CYP3A4, and combined use of breviscapine with simvastatin may improve the simvastatin efficacy and reduce its adverse reactions through reduced its dosage.

Determination of the acid values of edible oils via FTIR spectroscopy based on the OH stretching band.

A new method for determining the acid values (AVs) of edible oils based on the OH stretching band was developed. The oil sample was diluted with carbon tetrachloride and was placed in a quartz cuvette with a thickness of 1cm to record the FTIR spectrum. The peak at 3535cm(-1), which corresponds to the OH stretch of the carboxyl group in free fatty acids, together with the peak valley at 3508cm(-1) and the spectral data in the range of 3340-3390cm(-1) were used to determine the AV of the edible oil. The excellent linear relationship between the AVs measured in this work and those measured using a titration method, with a correlation coefficient (R) of 0.9929, indicates that the present procedure can be applied as an alternative to the classic method for determining the AVs of edible oils.

[Flavonoid glycosides from callus cultures of Dysosma versipellis].

Various chromatographic techniques, including silica gel column chromatography, Sephadex LH-20, preparative thin-layer chromatography, and preparative HPLC, were employed to isolate the chemical constituents from callus cultures of Dysosma versipellis. Structures of the compounds were elucidated based on UV, IR, MS and NMR spectroscopic data analysis. Totally, seven flavonoid glycosides were isolated from the 95% ethanol extract of the callus cultures and identified as kaempferol-3-O-[6″-(3″'-methoxy)-malonyl]-ß-D-glucopyranoside(1), kaempferol-3-O-(6″-O-acetyl)-ß-D-glucopyranoside(2), kaempferide-3-O-ß-D-glucopyranoside(3), kaempferol-3-O-ß-D-glucopyranoside(4), isoquercitrin(5), quercetin-4'-O-ß-D-glucopyranoside(6) and kaempferol-3-(6″-malonyl)-ß-D-glucopyranoside(7), respectively.All these compounds were isolated from callus cultures of D. versipellis for the first time.Compounds 1, 2, 3, 6 and 7 were firstly obtained from plant materials of D. versipellis, and compound 1 was a new compound.

Flavonol dimers from callus cultures of Dysosma versipellis and their in vitro neuraminidase inhibitory activities.

A chemical investigation of callus cultures of Dysosma versipellis led to the isolation of five new flavonol dimers, dysoverines A-E (1-5), together with 12 known compounds (6-17). The structures of new compounds were determined by the extensive spectroscopic data analyses. The biosynthetic pathway of the new compounds was proposed to involve O-methylation, prenylation, and Diels-Alder cycloaddition, which successively occurred in cultured plant cells. Compounds 1-17 exhibited in vitro neuraminidase inhibitory activities with the IC50 values of 31.0-93.9µM.

Ocular inflammation and endoplasmic reticulum stress are attenuated by supplementation with grape polyphenols in human retinal pigmented epithelium cells and in C57BL/6 mice.

Inflammation and endoplasmic reticulum (ER) stress are common denominators for vision-threatening diseases such as diabetic retinopathy and age-related macular degeneration. Based on our previous study, supplementation with muscadine grape polyphenols (MGPs) alleviated systemic insulin resistance and proinflammatory responses. In this study, we hypothesized that MGPs would also be effective in attenuating ocular inflammation and ER stress. We tested this hypothesis using the human retinal pigmented epithelium (ARPE-19) cells and C57BL/6 mice. In ARPE-19 cells, tumor necrosis factor-α-induced proinflammatory gene expression of interleukin (IL)-1ß, IL-6, and monocyte chemotactic protein-1 was decreased by 35.0%, 68.8%, and 62.5%, respectively, with MGP pretreatment, which was primarily due to the diminished mitogen-activated protein kinase activation and subsequent reduction of nuclear factor κ-B activation. Consistently, acute ocular inflammation and leukocyte infiltration were almost completely dampened (>95%) by MGP supplementation (100-200 mg/kg body weight) in C57BL/6 mice. Moreover, MGPs reduced inflammation-mediated loss of tight junctions and retinal permeability. To further investigate the protective roles of MGPs against ER stress, ARPE-19 cells were stimulated with thapsigargin. Pretreatment with MGPs significantly decreased the following: 1) ER stress-mediated vascular endothelial growth factor secretion (3.47 ± 0.06 vs. 1.58 ± 0.02 µg/L, P < 0.0001), 2) unfolded protein response, and 3) early apoptotic cell death (64.4 ± 6.85 vs. 33.7 ± 4.32%, P = 0.0003). Collectively, we have demonstrated that MGP is effective in attenuating ocular inflammation and ER stress. Our work also suggests that MGP may provide a novel dietary strategy to prevent vision-threatening retinal diseases.

Targeting chemophotothermal therapy of hepatoma by gold nanorods/graphene oxide core/shell nanocomposites.

Nanographene oxide (NGO) are highly suitable to be the shells of inorganic nanomaterials to enhance their biocompatibility and hydrophilicity for biomedical applications while retaining their useful photonic, magnetic, or radiological functions. In this study, a novel nanostructure with gold nanorods (AuNRs) encapsulated in NGO shells is developed to be an ultraefficient chemophotothermal cancer therapy agent. The NGO shells decrease the toxicity of surfactant-coated AuNRs and provide anchor points for the conjugation of hyaluronic acid (HA). The HA-conjugated NGO-enwrapped AuNR nanocomposites (NGOHA-AuNRs) perform higher photothermal efficiency than AuNRs and have the capability of targeting hepatoma Huh-7 cells. NGOHA-AuNR is applied to load doxorubicin (DOX), and it exhibits pH-responsive and near-infrared light-triggered drug-release properties. Chemophotothermal combined therapy by NGOHA-AuNRs-DOX performs 1.5-fold and 4-fold higher targeting cell death rates than single chemotherapy and photothermal therapy, respectively, with biosafety to nontargeting cells simultaneously. Furthermore, our strategy could be extended to constructing other NGO-encapsulated functional nanomaterial-based carrier systems.

Pharmacokinetic interaction between scutellarin and valsartan in rats.

Scutellarin is the main effective constituent of breviscapine, a flavonoid mixture isolated from the dried whole plant of Erigeron breviscapus (Vant.) Hand-Mazz, and valsartan is used as an antihypertensive drug. These two drugs have already been clinically used together to treat diabetic nephropathy (DN) in China, and the combined medications showed some enhanced protection against DN. The aim of this study is to investigate the potential pharmacokinetic interaction between scutellarin and valsartan in rats. Breviscapine injection (20 mg x kg(-1), i.v.) and valsartan (15 mg x kg-, i.g.), either alone or together were given to 18 male Sprague-Dawley rats. Concentrations of scutellarin and valsartan were quantified by HPLC, and pharmacokinetic parameters were calculated by non-compartmental methods. We found that the pharmacokinetic parameters of scutellarin altered significantly after co-administration of oral valsartan. The plasma clearance (CL(p)) and the bile clearance (CL(b)) of scutellarin were reduced significantly in the presence of valsartan. After oral administration of valsartan with or without intravenous scutellarin, however, the pharmacokinetic parameters of valsartan were comparable. In conclusion, our data suggests that the concurrent use of valsartan reduces the biliary excretion of scutellarin, and this may be due to the inhibitory effect of valsartan on the biliary excretion of scutellarin mediated by Mrp2 (Multidrug resistance-associated protein 2).