The Graphene Quantum Dots Gated Nanoplatform for Photothermal-Enhanced Synergetic Tumor Therapy.

Currently, the obvious side effects of anti-tumor drugs, premature drug release, and low tumor penetration of nanoparticles have largely reduced the therapeutic effects of chemotherapy. A drug delivery vehicle (MCN-SS-GQDs) was designed innovatively. For this, the mesoporous carbon nanoparticles (MCN) with the capabilities of superior photothermal conversion efficiency and high loading efficiency were used as the skeleton structure, and graphene quantum dots (GQDs) were gated on the mesopores via disulfide bonds. The doxorubicin (DOX) was used to evaluate the pH-, GSH-, and NIR-responsive release performances of DOX/MCN-SS-GQDs. The disulfide bonds of MCN-SS-GQDs can be ruptured under high glutathione concentration in the tumor microenvironment, inducing the responsive release of DOX and the detachment of GQDs. The local temperature of a tumor increases significantly through the photothermal conversion of double carbon materials (MCN and GQDs) under near-infrared light irradiation. Local hyperthermia can promote tumor cell apoptosis, accelerate the release of drugs, and increase the sensitivity of tumor cells to chemotherapy, thus increasing treatment effect. At the same time, the detached GQDs can take advantage of their extremely small size (5-10 nm) to penetrate deeply into tumor tissues, solving the problem of low permeability of traditional nanoparticles. By utilizing the photothermal properties of GQDs, synergistic photothermal conversion between GQDs and MCN was realized for the purpose of synergistic photothermal treatment of superficial and deep tumor tissues.

Enterohemorrhagic Escherichia coli O157:H7 antigens produced in transgenic lettuce effective as an oral vaccine in mice.

KEY MESSAGE: Transgene with recombination sites to address biosafety concerns engineered into lettuce to produce EspB and γ-intimin C280 for oral vaccination against EHEC O157:H7. Enterohemorrhagic Escherichia coli (EHEC) O157:H7 is a food-borne pathogen where ruminant farm animals, mainly bovine, serve as reservoirs. Bovine vaccination has been used to prevent disease outbreaks, and the current method relies on vaccines subcutaneously injected three times per year. Since EHEC O157:H7 colonizes mucosal surfaces, an oral vaccine that produces an IgA response could be more convenient. Here, we report on oral vaccination against EHEC O157:H7 in mice orally gavaged with transgenic lettuce that produces EHEC O157:H7 antigens EspB and γ-intimin C280. Younger leaves accumulated a higher concentration of antigens; and in unexpanded leaves of 30-day-old T2 plants, EspB and γ-intimin C280 were up to 32 and 51 µg/g fresh weight, respectively. Mice orally gavaged with lettuce powders containing < 3 µg antigens for 6 days showed a mucosal immune response with reduced colonization of EHEC O157:H7. This suggests that the transgenic lettuce has potential to be used for bovine vaccination. To promote the biosafety of crop plants producing medically relevant proteins, recombination sites were built into our transgenic lines that would permit optional marker removal by Cre-lox recombination, as well as transgene deletion in pollen by CinH-RS2 recombination. The ability to upgrade the transgenic lettuce by stacking additional antigen genes or replacing older genes with newer versions would also be possible through the combined use of Bxb-att and Cre-lox recombination systems.

Synergistic Amplification of Ferroptosis with Liposomal Oxidation Catalyst and Gpx4 Inhibitor for Enhanced Cancer Therapy.

As a distinctly different way from apoptosis, ferroptosis can cause cell death through excessive accumulation of lipid peroxide (LPO) and show great potential for cancer therapy. However, efficient strategies for ferroptosis therapy are still facing great challenges, mainly due to insufficient endogenous H2 O2 or relatively high pH value for Fenton reaction-dependent ferroptosis, and the high redox level of tumor cells attenuates the oxidation therapy. Herein, an efficient lipid-based delivery system to load oxidation catalyst and glutathione peroxidase 4 (Gpx4) inhibitor is orchestrated, intending to amplify Fenton reaction-independent ferroptosis by bidirectional regulation of LPO accumulation. Ferric ammonium citrate (FAC), Gpx4 inhibitor sorafenib (SF), and unsaturated lipids are constructed into mPEG2K -DSPE-modified liposomes (Lip@SF&FAC). Influenced by the high level of intratumoral glutathione, FAC can be converted into Fe2+ , and subsequently the formed iron redox pair (Fe2+ /Fe3+ ) catalyzes unsaturated phospholipids of liposomes into LPO via a Fenton reaction-independent manner. Meanwhile, SF can downregulate LPO reduction by inhibiting Gpx4 activation. In vitro and in vivo antitumor experiments show that Lip@SF&FAC induces massive LPO accumulation in tumor cells and ultimately exhibits strong tumor-killing ability with negligible side effect. Consequently, this two-pronged approach provides a new ferroptosis strategy for predominant LPO accumulation and enhanced cancer therapy.

Recurrent intestinal ulcer with bloody stool for >10 years in an adolescent boy of 15 years: A case report.

RATIONALE: Infectious diseases, autoimmune diseases and vascular diseases can lead to intestinal ulcers, and inflammatory bowel disease is typically suspected as the underlying cause of ulcer and bleeding from the intestinal ulcers leading to bloody stool, and malnutrition. Here we report a rare case of successfully treated case of intestinal ulcer, bloody stool, and malnutrition by dietary modification and avoidance of long term barbecued spicy food and carbonated drinks. PATIENT CONCERNS: A 15-year-old male patient had repeated symptoms of blood in the stool for >10 years. Treatment for Chron's disease was not successful. An exhaustive investigation failed to confirm the diagnosis. DIAGNOSIS INTERVENTIONS: Through changing diet structure, avoiding spicy food, and supplementing enteral nutrition and recurrent glutamine. OUTCOMES: The patient's symptoms improved significantly, and the intestinal ulcer healed under endoscope. LESSONS: Pay attention to healthy diet in life and avoid long-term consumption of spicy food and carbonated drinks.

Effects of low-dose B vitamins plus betaine supplementation on lowering homocysteine concentrations among Chinese adults with hyperhomocysteinemia: a randomized, double-blind, controlled preliminary clinical trial.

PURPOSE: To test the hypothesis that daily supplementation with low-dose B vitamins plus betaine could significantly reduce plasma homocysteine concentrations in Chinese adults with hyperhomocysteinemia and free from background mandatory folic acid fortification. METHODS: One hundred apparently healthy adults aged 18-65 years with hyperhomocysteinemia were recruited in South China from July 2019 to June 2021. They were randomly assigned to either the supplement group (daily supplementation: 400 µg folic acid, 8 mg vitamin B6, 6.4 µg vitamin B12 and 1 g betaine) or the placebo group for 12 weeks. Fasting venous blood was collected at baseline, week 4 and week 12 to determine the concentrations of homocysteine, folate, vitamin B12 and betaine. Generalized estimation equations were used for statistical analysis. RESULTS: Statistically significant increments in blood concentrations of folate, vitamin B12 and betaine after the intervention in the supplement group indicated good participant compliance. At baseline, there were no significant differences in plasma homocysteine concentration between the two groups (P = 0.265). After 12-week supplementation, compared with the placebo group, there was a significant reduction in plasma homocysteine concentrations in the supplement group (mean group difference - 3.87; covariate-adjusted P = 0.012; reduction rate 10.1%; covariate-adjusted P < 0.001). In the supplement group, the decreased concentration of plasma homocysteine was associated with increments of blood concentrations of both folate (ß = -1.680, P = 0.004) and betaine (ß = -1.421, P = 0.020) after 12 weeks of supplementation. CONCLUSIONS: Daily supplementation with low-dose B vitamins plus betaine for 12 weeks effectively decreased plasma homocysteine concentrations in Chinese adults with hyperhomocysteinemia. TRIAL REGISTRATION: This trial was registered at clinicaltrials.gov as NCT03720249 on October 25, 2018. Website: https://clinicaltrials.gov/ct2/show/NCT03720249 .

Combinations of scalp acupuncture location for the treatment of post-stroke hemiparesis: A systematic review and Apriori algorithm-based association rule analysis.

Background: Post-stroke hemiparesis strongly affects stroke patients' activities of daily living and health-related quality of life. Scalp acupuncture (SA) is reportedly beneficial for post-stroke hemiparesis. However, there is still no standard of SA for the treatment of post-stroke hemiparesis. Apriori algorithm-based association rule analysis is a kind of "if-then" rule-based machine learning method suitable for investigating the underlying rules of acupuncture point/location selections. This study aimed to investigate the core SA combinations for the treatment of post-stroke hemiparesis by using a systematic review and Apriori algorithm-based association rule analysis. Methods: We conducted a systematic review to include relevant randomized controlled trial (RCT) studies investigating the effects of SA treatment in treating patients with post-stroke hemiparesis, assessed by the Fugl-Meyer Assessment (FMA) score. We excluded studies using herbal medicine or manual acupuncture. Results: We extracted 33 SA locations from the 35 included RCT studies. The following SA styles were noted: International Standard Scalp Acupuncture (ISSA), WHO Standard Acupuncture Point Locations (SAPL), Zhu's style SA, Jiao's style SA, and Lin's style SA. Sixty-one association rules were investigated based on the integrated SA location data. Conclusions: SAPL_GV20 (Baihui), SAPL_GV24 (Shenting), ISSA_MS6_i (ISSA Anterior Oblique Line of Vertex-Temporal, lesion-ipsilateral), ISSA_MS7_i (ISSA Posterior Oblique Line of Vertex-Temporal, lesion-ipsilateral), ISSA_PR (ISSA Parietal region, comprised of ISSA_MS5, ISSA_MS6, ISSA_MS7, ISSA_MS8, and ISSA_MS9), and SAPL_Ex.HN3 (Yintang) can be considered the core SA location combination for the treatment of post-stroke hemiparesis. We recommend a core SA combination for further animal studies, clinical trials, and treatment strategies.

An Apriori Algorithm-Based Association Rule Analysis to Identify Herb Combinations for Treating Uremic Pruritus Using Chinese Herbal Bath Therapy.

Uremic pruritus (UP) is prevalent among patients with end-stage renal disease (ESRD), which causes severe itching and affects their quality of life. Additionally, patients experience fatigue and depression, and an increased risk of mortality has also been reported. A meta-analysis of 17 randomized controlled trials (RCTs) has indicated that Chinese herbal bath therapy (CHBT) had adjuvant benefits in improving UP in ESRD patients, and previous studies have reported that herb combinations were more useful than treatment with a single herb. Association rule analysis has been used to evaluate potential correlations between herb combinations, and Apriori algorithms are one of the most powerful machine-learning algorithms available for identifying associations within databases. Therefore, we used the Apriori algorithm to analyze association rules of potential core herb combinations for use in CHBT for UP treatment using data from a meta-analysis of 17 RCTs that used CHBT for UP treatment. Data on 43 CHBT herbs were extracted from 17 RCTs included for analysis and we found 19 association rules. The results indicated that the following herb combinations {Chuanxiong, Baijili} ≥ {Dahuang} and {Dahuang, Baijili} ≥ {Chuanxiong} were most strongly associated, implying that these herb combinations represent potential CHBT treatments for UP.

Effects of light irradiation on essential oil biosynthesis in the medicinal plant Asarum heterotropoides Fr. Schmidt var. mandshuricum (Maxim) Kitag.

Asarum heterotropoides Fr. var. mandshuricum (Maxim) Kitag (Chinese wild ginger) is an important medicinal herb. Essential oil extracted from its roots is the key ingredient and is mainly composed of phenylpropanoid compounds. As a skiophyte plant, light is a crucial factor for A. heterotropoides var. mandshuricum growth and metabolism. To investigate the effects of light irradiation on the essential oil biosynthesis in A. heterotropoides var. mandshuricum, the plants were cultivated in four light irradiation treatments (100, 50, 24 and 12% full sunlight). The photosynthetic capacity, essential oil content and composition, activities of several enzymes and levels of some secondary metabolites involved in the shikimic acid and cinnamic acid pathways were analyzed. The leaf mass per area, average diurnal net photosynthetic rate, and the essential oil content increased significantly with increasing light intensity. Phenylalanine, cinnamic acid, and p-coumaric acid in the cinnamic acid pathway were at their highest levels in plants cultivated in 100% full sunlight. The highest content of shikimic acid in the shikimic acid pathway was obtained in plants grown in 50% sunlight transmittance. The activity of the enzymes 3-Deoxy-D-arabino-heptulosonate-7-phosphate synthase, phenylalanine ammonia lyase, cinnamate-4-hydroxylase and 4-coumarate:CoA ligase increased proportionally with light intensity. Overall, we conclude that high light irradiation promotes high net photosynthetic rate, high activity of enzymes and high amounts of phenylpropanoid precursor metabolites leading to significant biosynthesis of essential oil in A. heterotropoides var. mandshuricum.

Network pharmacology suggests biochemical rationale for treating COVID-19 symptoms with a Traditional Chinese Medicine.

Chinese herbal formulas including the lung-cleaning and toxicity-excluding (LCTE) soup have played an important role in treating the ongoing COVID-19 pandemic (caused by SARS-CoV-2) in China. Applying LCTE outside of China may prove challenging due to the unfamiliar rationale behind its application in terms of Traditional Chinese Medicine. To overcome this barrier, a biochemical understanding of the clinical effects of LCTE is needed. Here, we explore the chemical compounds present in the reported LCTE ingredients and the proteins targeted by these compounds via a network pharmacology analysis. Our results indicate that LCTE contains compounds with the potential to directly inhibit SARS-CoV-2 and inflammation, and that the compound targets proteins highly related to COVID-19's main symptoms. We predict the general effect of LCTE is to affect the pathways involved in viral and other microbial infections, inflammation/cytokine response, and lung diseases. Our work provides a biochemical basis for using LCTE to treat COVID-19 and its main symptoms.

Application of high-speed counter-current chromatography and HPLC to separate and purify of three polyacetylenes from Platycodon grandiflorum.

Three polyacetylenes were isolated and purified from Platycodon grandiflorum A. DC for the first time by high-speed counter-current chromatography using a two-phase solvent system composed of hexane/ethyl acetate/methanol/water (1:31:1:31, v/v/v/v) and high-performance liquid chromatography with an Agilent ZORBAX® SB-C18 column (4.6 mm × 150 mm, 5 µm). After separation by high-speed counter-current chromatography and high-performance liquid chromatography, we obtained 3.5 mg of platetyolin A, 4.1 mg of platetyolin B, and 18.1 mg of lobetyolin with purities of 97.2, 96.7, and 96.9%, respectively. The purity of each compound was assessed by high-performance liquid chromatography and the chemical structures were evaluated by high-resolution electrospray ionization time-of-flight mass spectrometry and one- and two-dimensional NMR spectroscopy. Among the isolated compounds, platetyolin A and platetyolin B are newly reported compounds.

A chemometric-assisted LC-MS/MS method for the simultaneous determination of 17 limonoids from different parts of Xylocarpus granatum fruit.

The marine mangrove Xylocarpus granatum is used as a folk medicine and is rich in bioactive limonoids. The quantitative determination of the chemical composition and distribution of limonoids in different parts of X. granatum fruit (fruit peel, seed coat, seed kernels, seed, and fruit) is significant for authentication and quality control purposes. However, the quantitative determination of limonoids in X. granatum has not yet been reported. In this study, a chemometric-assisted liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous determination of 17 limonoids to reveal the chemical composition and distribution in different parts of X. granatum fruit. Ultrasonic-assisted extraction, optimized by response surface methodology (RSM), was more accurate than the general one-variable-at-a-time method. The overall distribution of 17 limonoids in different parts of X. granatum fruit had the following order: seed kernels > seed > fruit, and 13 limonoids showed a rank order of seed kernels > seed > fruit > fruit peel > seed coat. Furthermore, principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were used to analyze the LC-MS/MS data and provide a chemometric model for easy visualization and interpretation to classify the different parts of X. granatum fruit. In addition, the study indicated that the chemometric-assisted strategy, consisting of RSM, PCA, and OPLS-DA for the development, optimization, and data analysis of multicomponent quantitation by LC-MS/MS, is effective and feasible. This study provided the chemical composition and distribution evidence for the authentication and quality control of X. granatum fruit.

Study on the metabolites of isoalantolactone in vivo and in vitro by ultra performance liquid chromatography combined with Triple TOF mass spectrometry.

Isoalantolactone (IAL) is an active sesquiterpene naturally present in many vegetables, condiments and medicinal plants. In this study, an efficient strategy was developed for the identification of metabolites following the in vivo metabolism and in vitro biotransformation of IAL with rat intestinal bacteria utilizing ultra performance liquid chromatography combined with Triple TOF mass spectrometry (UPLC-Triple TOF-MS/MS). As a result, 46 metabolites including 34 novel sulfur-containing products were identified. The results demonstrated that IAL could undergo general metabolic reactions, including oxidation, hydration, hydrogenation, demethylation, cysteine conjugation and N-acetylcysteine conjugation, but the most noticeable characteristic of IAL metabolism was the H2S addition to the double bond between C-11 and C-13 and subsequent reactions to produce a series of novel sulfur-containing dimers. This is the first study of IAL metabolism in vivo, whose results provide novel and useful data for a better understanding of the safety and efficacy of IAL.

Polyhydroxytriterpenoids and Phenolic Constituents from Forsythia suspensa (Thunb.) Vahl Leaves.

Forsythia suspensa (Thunb.) Vahl leaves have been consumed in China as a health-promoting functional tea for centuries. Three new polyhydroxytriterpenoid glycosides named suspensanosides A-C (1-3), seven known polyhydroxytriterpenoids (4-10), and 12 known phenolics (11-22) were identified from F. suspensa leaves. Compounds 1-10, 15-17, and 22 have not been found in the Forsythia genus previously, whereas compound 14 was first reported to be isolated from the leaves of F. suspensa. All isolates were tested for their antiproliferative activities on BGC-823 and MCF-7 human tumor cell lines, whereas all phenolics were further investigated for their antioxidant activities by a DPPH assay. The results clearly demonstrate that triterpenoids, especially ursane-type triterpenoids, and the diverse phenolic components are crucial for the beneficial effects of F. suspensa leaves.

Apoptosis induced by Ginkgo biloba (EGb761) in melanoma cells is Mcl-1-dependent.

Melanoma is an aggressive skin cancer. Unfortunately, there is currently no chemotherapeutic agent available to significantly prolong the survival of the most patients with metastatic melanomas. Here we report that the Ginkgo biloba extract (EGb761), one of the most widely sold herbal supplements in the world, potently induces apoptosis in human melanoma cells by disturbing the balance between pro- and anti-apoptosis Bcl-2 family proteins. Treatment with EGb761 induced varying degrees of apoptosis in melanoma cell lines but not in melanocytes. Induction of apoptosis was caspase-dependent and appeared to be mediated by the mitochondrial pathway, in that it was associated with reduction in mitochondrial membrane potential and activation of Bax and Bak. Although EGb761 did not cause significant change in the expression levels of the BH3-only Bcl-2 family proteins Bim, Puma, Noxa, and Bad, it significantly downregulated Mcl-1 in sensitive but not resistant melanoma cells, suggesting a major role of Mcl-1 in regulating apoptosis of melanoma cells induced by EGb761. Indeed, siRNA knockdown of Mcl-1 enhanced EGb761-induced apoptosis, which was associated with increased activation of Bax and Bak. Taken together, these results demonstrate that EGb761 kills melanoma cells through the mitochondrial apoptotic pathway, and that Mcl-1 is a major regulator of sensitivity of melanoma cells to apoptosis induced by EGb761. Therefore, EGb761 with or without in combination with targeting Mcl-1 may be a useful strategy in the treatment of melanoma.

PPARγ agonist from Chromolaena odorata.

A phytochemical investigation of Chromolaena odorata resulted in the isolation of five new compounds, 5aα,6,9,9aß,10-pentahydro-10ß-hydroxy-7-methylanthra[1,2-d][1,3]dioxol-5-one (1), 1,2-methylenedioxy-6-methylanthraquinone (2), 3-hydroxy-1,2,4-trimethoxy-6-methylanthraquinone (3), 3-hydroxy-1,2-dimethoxy-6-methylanthraquinone (4), and 7-methoxy-7-epi-medioresinol (5), together with 12 known compounds, odoratin (6), 3ß-acetyloleanolic acid (7), ursolic acid (8), ombuin (9), 4,2'-dihydroxy-4',5',6'-trimethoxychalcone (10), (-)-pinoresinol (11), austrocortinin (12), tianshic acid (13), cleomiscosin D (14), (-)-medioresinol (15), (-)-syringaresinol (16), and cleomiscosin A (17). All the compounds were evaluated for their PPARγ transactivation activity, and compound 6 showed moderate activity with an EC(50) value of 3.10 µM.

Novel taxa-4(20),12-diene and 2(3→20)abeotaxane from needles of Taxus canadensis.

A novel 6/8/6-membered taxane with a rare C-12(13)-double bond and rare 2(3→20)abeotaxane were isolated from the needles of Taxus canadensis. Their structures were characterized as 7ß,9α,10ß-triacetoxytaxa-4(20),12-diene-2α,5α,11ß-triol (1) and 2α,7ß,10ß-triacetoxy-5α-hydroxy-2(3→20)abeotaxa-4(20),11-diene-9,13-dione (2) on the basis of 1D and 2D spectroscopic data. 1 is the first example of a natural taxane without substitution at both C-13 and C-14.

A novel taxane 13-glucoside and other taxanes from the leaves of Taxus cuspidata.

Three new taxanes, 2 α,9 α,10 ß-triacetoxy-13 α-( ß-D-glucopyranosyloxy)taxa-4(20),11-dien-5 α-ol, 5 α,10 ß,13 α-triacetoxytax-11-ene-2 α,7 ß,9 α,20-tetraol, and 5 α,10 ß,13 ß-triacetoxy-2 α,7 ß-dihydroxy-2(3→20) abeotaxa-4(20),11-dien-9-one, were isolated from the leaves of the Japanese yew, Taxus cuspidata. Compound 1 is the first example of a taxane with 13-glycosidic linkage.

Secondary metabolites of plants from the genus Saussurea: chemistry and biological activity.

The Asteraceae family comprises ca. 1000 genera, mainly distributed in Asia and Europe. Saussurea DC., as the largest subgenus of this family, comprises ca. 400 species worldwide, of which ca. 300 species occur in China. Most plants in China grow wild in the alpine zone of the Qingzang Plateau and adjacent regions at elevations of 4000 m. Plants of the genus Saussurea (Asteraceae) are used in both traditional Chinese folk medicine and Tibet folklore medicine, since they are efficacious in relieving internal heat or fever, harmonizing menstruation, invigorating blood circulation, stopping bleeding, alleviating pain, increasing energy, and curing rheumatic arthritis. A large number of biologically active compounds have been isolated from this genus. This review shows the chemotaxonomy of these compounds (215 compounds) such as sesquiterpenoids (101 compounds), flavonoids (19 compounds), phytosterols (15 compounds), triterpenoids (25 compounds), lignans (32 compounds), phenolics (23 compounds), and chlorophylls (11 compounds). Biological activities (anti-inflammatory, anticancer, antitumor, hepatoprotective, anti-ulcer, cholagogic, immunosuppressive, spasmolytic, antimicrobial, antiparasitic, antifeedant, CNS depressant, antioxidant, etc.) of these compounds, including structure-activity relationships, are also discussed.

A new metabolite with a new substitution pattern from the seeds of the Chinese Yew, Taxus mairei.

A new taxoid metabolite with a new substitution pattern was isolated from the methanol extract of the seeds of Taxus mairei, and its structure was established as 5alpha,15-dihydroxy-7beta,9alpha-diacetoxy-11(15-->1)abeo-taxa-4(20),11-dien-13-one (1) on the basis of spectral analysis including (1)H- and (13)C-NMR, HMQC, HMBC, NOESY, and confirmed by HR-FAB mass spectrometry.