Efficacy of intravenous vitamin C intervention for septic patients: A systematic review and meta-analysis based on randomized controlled trials.

BACKGROUND: The role of vitamin C in sepsis is still controversial, we aimed to systematically review the efficacy of intravenous vitamin C supplementation in the treatment of sepsis. METHODS: MEDLINE, EmBase, Web of Science, WanFang Data and CNKI were comprehensively searched to collect randomized controlled trails (RCTs) of vitamin C supplementation for patients with sepsis or sepsis shock from January 2000 to March 2021. Two researchers independently screened the literature, extracted the data and accessed the risk of bias in the included studies; meta-analysis was then performed by using Revman 5.4 software. RESULTS: A total of 10 RCTs involving 1400 participants were included. The results of meta-analysis showed that intravenous vitamin C supplementation can improve SOFA (ΔSOFA) within 72 h [RR = 1.32,95% CI(0.80,1.85), P < 0.0001] of septic patients. There were no difference on short term mortality (28-30d)[RR = 0.83,95% CI(0.65,1.05), P = 0.11], long term mortality (90d) [RR = 1.16,95% CI(0.82,1.66), P = 0.40], hospital LOS[RR = 0.15,95% CI(-0.73,1.03), P = 0.55], ventilator-free days[RR = 0.09,95% CI(-0.24,0.42), P = 0.60], ICU-LOS[RR = 0.22,95% CI(-0.13,0.57), P = 0.22], between two groups. The results of Subgroup analysis showed that intravenous vitamin C alone can reduce the risk of short term mortality (28-30d) [RR = 0.61,95% CI(0.47,0.79), P = 0.0002]of sepsis patients. CONCLUSION: Based on current RCTs, our work indicated that mono-intravenous vitamin C therapy may reduce short-term mortality of sepsis patients, and it may protect organ functions. Due to the limitation of the quantity and quality of included studies, the above conclusions need to be verified by more large scale and high quality randomized control trials.

[A new antiviral isoquinoline alkaloid from Thalictrum glandulosissimum].

A new isoquinoline alkaloid(1) has been isolated from the whole plant of Thalictrum glandulosissimum by using various chromatographic techniques, including silica gel, sephadex, MCI-gel resin, and RP-HPLC, and its structure was determined as 1-(6-hydroxy-7-methylisoquinolin-1-yl) ethantone by physicochemical properties and spectroscopic data. This compound was evaluated for anti-tobacco mosaic virus(TMV) activity. The results showed that it had prominent anti-TMV activity with inhibition rates of 28.4%. This rate was closed to that of positive control.

[A new antimicrobial isobenzoisofuran compound from Cassia pumila].

A new isobenzoisofuran(1) has been isolated from the whole plant of Cassia pumila using various chromatographic techniques, including silica gel, Sephadex, MCI-gel resin, and RP-HPLC, and its structure was determined as 9-(2-hydroxyethyl)-2,2-dimethyl-2H-furo[3,4-g]chromen-6(8H)-one. This compound was also evaluated for its antibacterial activity. The results showed that it had prominent antibacterial activity with MIC_(90) value of(45.2±4.2) µg·mL~(-1) for methicillin resistant Staphylococcus aureus(MRSA) strain. This value was closed to that of levofloxacin [with MIC_(90) value(48.5±4.3) µg·mL~(-1)].

[A new cytotoxic flavone from Cassia nomame].

A new flavone( 1) has been isolated from the whole plant of Cassia nomame by using various chromatographic techniques,including silica gel,Sephadex,MCI-gel resin,and RP-HPLC,and its structure was determined as 8,4'-dimethoxy-7-( 2-oxopropyl)-flavone based on spectroscopic data. The biological activity test showed that this compound displayed potent cytotoxicity against NB4,SH-SY5 Y,PC3,A549 and MCF-7 cell lines with IC50 values 2. 2,1. 8,3. 4,4. 5 and 1. 6 µmol·L-1,respectively.

[A new isobenzofuranone derivative from Chaenomeles sinensis and its antibacterial activity].

A new isobenzofuranone derivative was isolated from Chaenomeles sinensis by using various chromatographic techniques,including silica gel,Sephadex LH-20,MCI-gel resin and RP-HPLC. This compound was determined as 2,2-dimethyl-5-( 2-oxopropyl)-2 H-furo[3,4-h]chromen-7( 9 H)-one( 1) by NMR,MS,IR and UV spectra,and was also evaluated for its antibacterial activity. The results showed that it showed prominent antibacterial activity with MIC90 value of( 53. 7±4. 5) mg·L-1 for methicillin resistant Staphylococcus aureus( MRSA) strain. This value is close to that of levofloxacin [with MIC90 value( 50. 2± 4. 2) mg·L-1].

Inhibition of mutant Kras and p53-driven pancreatic carcinogenesis by atorvastatin: Mainly via targeting of the farnesylated DNAJA1 in chaperoning mutant p53.

Recent studies have indicated that using statins to inhibit the mevalonate pathway induces mutant p53 degradation by impairing the interaction of mutant p53 with DnaJ subfamily A member 1 (DNAJA1). However, the role of the C-terminus of DNAJA1 with a CAAX box for farnesylation in the binding, folding, and translocation of client proteins such as mutant p53 is not known. In the present study, we used a genetically engineered mouse model of pancreatic carcinoma and showed that atorvastatin significantly increased animal survival and inhibited pancreatic carcinogenesis. There was a dramatic decrease in mutant p53 protein accumulation in the pancreatic acini, pancreas intraepithelial neoplasia lesions, and adenocarcinoma. Supplementation with farnesyl pyrophosphate, a substrate for protein farnesylation, rescued atorvastatin-induced mutant p53 degradation in pancreatic cancer cells. Tipifarnib, a farnesyltransferase inhibitor, mirrored atorvastatin's effects on mutant p53, degraded mutant p53 in a dose-dependent manner, and converted farnesylated DNAJA1 into unfarnesylated DNAJA1. Farnesyltransferase gene knockdown also significantly promoted mutant p53 degradation. Coimmunoprecipitation either by an anti-DNAJA1 or p53 antibody confirmed the direct interaction of mutant p53 and DNAJA1 and higher doses of atorvastatin treatments converted more farnesylated DNAJA1 into unfarnesylated DNAJA1 with much less mutant p53 pulled down by DNAJA1. Strikingly, C394S mutant DNAJA1, in which the cysteine of the CAAX box was mutated to serine, was no longer able to be farnesylated and lost the ability to maintain mutant p53 stabilization. Our results show that farnesylated DNAJA1 is a crucial chaperone in maintaining mutant p53 stabilization and targeting farnesylated DNAJA1 by atorvastatin will be critical for inhibiting p53 mutant cancer.

Inhibition of Pancreatic Carcinoma Growth Through Enhancing ω-3 Epoxy Polyunsaturated Fatty Acid Profile by Inhibition of Soluble Epoxide Hydrolase.

BACKGROUND/AIM: Cytochrome P450 epoxygenase is a major enzyme involved in the metabolism of ω-3 polyunsaturated fatty acids (PUFAs) to produce biologically active ω-3 epoxy fatty acids (ω-3 epoxides). In general, all epoxy PUFAs including ω-3 epoxides are quickly metabolized/inactivated by soluble epoxide hydrolase (sEH) to form diol products. The aims of this study were to determine the effect and mechanism of fat-1 transgene, and ω-3 PUFA combined with sEH gene knockout or inhibitor on inhibiting pancreatic cancer and the related mechanisms involved. MATERIALS AND METHODS: PK03-mutant KrasG12D murine pancreatic carcinoma cells were inoculated into mouse models including fat-1, sEH-/- and C57BL/6J mice. The mice were fed with AIN-76A diet with or without ω-3 PUFA supplementation or treated with sEH inhibitor. In addition to tumor growth (tumor size and weight), cell proliferation, mutant Kras-mediated signaling, inflammatory reaction and angiogenesis were analyzed immunohisto-chemically and by western blot assay. ω-3 PUFA metabolism, particularly focusing on ω-3 epoxy fatty acids (ω-3 epoxides), was measured using a liquid chromatography with tandem mass spectrometry (LC-MS/MS) approach. RESULTS: Significant decreases of weight and size of the PK03 pancreatic carcinoma were observed in the fat-1 transgenic mice treated with sEH inhibitor compared to those of C57BL/6J control mice fed with AIN-76A diet (weight: 0.28±0.04 g vs. 0.58±0.06 g; size: 187.0±17.5 mm3 vs. 519.3±60.6 mm3). In a separate experiment, sEH-/- mice fed ω-3 PUFA supplement and C57BL/6J mice treated with sEH inhibitor and fed ω-3 PUFA supplement exhibited a significant reduction in the weight and size of the pancreatic carcinoma compared to C57BL/6J control mice (weight: 0.26±.26 g and 0.39±.39 g vs. 0.69±0.11 g, respectively; size: 274.2±36.2 mm3 and 296.4±99.8 mm3 vs. 612.6±117.8 mm3, respectively). Moreover, compared to the pancreatic tumors in C57BL/6J control mice, the tumors in fat-1 transgenic mice treated with sEH inhibitor showed a significant less inflammatory cell infiltrate (62.6±9.2/HPF (high power field) vs. 8.0±1.2/HPF), tumor cell proliferation (48.5±1.7% vs. 16.5±1.6%), and angiogenesis (micro-vessel density (MVD): 35.0±1.0 vs. 11.1±0.5) immunohistochemically, as well as significantly increased caspase-3 labeled apoptosis (0.44±0.06% vs. 0.69±0.06%, respectively). Using western blot approach, significant inhibition of mutant Kras-activated signals including phosphorylated Serine/threonine kinases (cRAF), Mitogen-activated protein kinase kinase (MEK), and extracellular signal-regulated kinase (ERK) were identified in pancreatic carcinoma of fat-1 transgenic mice treated with sEH inhibitor. Eicosanoic acid metabolic profiling of the serum specimens detected a significant increase of the ratios of epoxides to dihydroxy fatty acid (DiHDPE) for docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), and epoxides/dihydroxy octadecenoic acid (DiHOME) for arachidonic acid (ARA) and linoleic acid (LA), as well as a significant increase of epoxy metabolites of DHA, EPA, ARA and LA in fat-1 transgenic mice treated with a sEH inhibitor. CONCLUSION: ω-3 epoxy products from ω-3 PUFA metabolism play a crucial role in inhibiting pancreatic cancer growth, and use of ω-3 PUFAs combined with sEH inhibition is a strategy with high potential for pancreatic cancer treatment and prevention.

Tumour-specific amplitude-modulated radiofrequency electromagnetic fields induce differentiation of hepatocellular carcinoma via targeting Cav3.2 T-type voltage-gated calcium channels and Ca2+ influx.

BACKGROUND: Administration of amplitude modulated 27·12 MHz radiofrequency electromagnetic fields (AM RF EMF) by means of a spoon-shaped applicator placed on the patient's tongue is a newly approved treatment for advanced hepatocellular carcinoma (HCC). The mechanism of action of tumour-specific AM RF EMF is largely unknown. METHODS: Whole body and organ-specific human dosimetry analyses were performed. Mice carrying human HCC xenografts were exposed to AM RF EMF using a small animal AM RF EMF exposure system replicating human dosimetry and exposure time. We performed histological analysis of tumours following exposure to AM RF EMF. Using an agnostic genomic approach, we characterized the mechanism of action of AM RF EMF. FINDINGS: Intrabuccal administration results in systemic delivery of athermal AM RF EMF from head to toe at levels lower than those generated by cell phones held close to the body. Tumour shrinkage results from differentiation of HCC cells into quiescent cells with spindle morphology. AM RF EMF targeted antiproliferative effects and cancer stem cell inhibiting effects are mediated by Ca2+ influx through Cav3·2 T-type voltage-gated calcium channels (CACNA1H) resulting in increased intracellular calcium concentration within HCC cells only. INTERPRETATION: Intrabuccally-administered AM RF EMF is a systemic therapy that selectively block the growth of HCC cells. AM RF EMF pronounced inhibitory effects on cancer stem cells may explain the exceptionally long responses observed in several patients with advanced HCC. FUND: Research reported in this publication was supported by the National Cancer Institute's Cancer Centre Support Grant award number P30CA012197 issued to the Wake Forest Baptist Comprehensive Cancer Centre (BP) and by funds from the Charles L. Spurr Professorship Fund (BP). DWG is supported by R01 AA016852 and P50 AA026117.

[A new naphthaldehyde derivative from Comastoma pulmonarium and its anti-tobacco mosaic virus (anti-TMV) activity].

A new naphthaldehyde derivative has been isolated from Comastoma pulmonarium by using various chromatographic techniques, including silica gel, Sephadex LH-20, MCI-gel resin and RP-HPLC. This compounds was determined as 5-methoxy-2-methyl-7-(2-oxopropyl)naphthalene-1-carbaldehyde(1) by NMR, MS, IR and UV spectra. This compound was also evaluated for its anti-tobacco mosaic virus (anti-TMV) activity. The result showed that it showed high anti-TMV activity with inhibition rate of 32.8%. The inhibition rate is close to that of positive control (ningnanmycin).

[A new isobenzofuranone derivative from Phlomis betonicoides and its antibacterial activity].

A new isobenzofuranone derivative has been isolated from Phlomis betonicoides by using various chromatographic techniques, including silica gel, Sephadex LH-20, MCI-gel resin and RP-HPLC. This compound was determined as 5-(3-hydroxypropyl)-2,2-dimethyl-2H-furo[3,4-h]chromen-7(9H)-one (1) by NMR, MS, IR and UV spectroscopic data. Compound 1 showed potent antibacterial activity with an MIC90 value of (58.4 ± 4.2) mg·L⁻¹ for methicillin resistant Staphylococcus aureus (MRSA) strain [levofloxacin as a control with MIC90 value of (52.8±4.6) mg·L⁻¹].

[A new isoflavone derivative from Rosa Damascena and its antibacterial activity].

A new isoflavone derivative was isolated from Rosa damascena by using various chromatographic techniques including silica gel, Sephadex LH-20, and preparative RP-HPLC separation. Its structure was identified as 4'-hydroxy-7-(3-hydroxypropanoyl)-6-methoxy-isoflavone using combined examinations of their UV, IR, MS, and NMR spectroscopic data. Biological activity test showed that this compound showed prominent antibacterial activity with MIC90 value of (46±4) mg·L⁻¹ for methicillin resistant Staphylococcus aureus(MRSA) strain. This value is close to that of levofloxacin [with MIC90 value (53±5) mg·L⁻¹].

[A new naphthalene derivative from Aloe vera and its antibacterial activity].

A new naphthalene derivative has been isolated from Aloe vera by using various chromatographic techniques, including silica gel, sephadex, MCI-gel resin, and RP-HPLC. The new compound was determined as 3-hydroxy-1-(1,7-dihydroxy-3,6-dimethoxynaphthalen-2-yl)propan-1-one (1). In the biological activity assay, compound 1 disglayed prominent antibacterial activity with a MIC90 value of (48±4) mg•L⁻¹ for methicillin resistant Staphylococcus aureus (MRSA) strain which was stronger than that of the positive control levofloxacin with a MIC90 value (58±5) mg•L⁻¹.

Biosynthesis of plant-derived ginsenoside Rh2 in yeast via repurposing a key promiscuous microbial enzyme.

Ginsenoside Rh2 is a potential anticancer drug isolated from medicinal plant ginseng. Fermentative production of ginsenoside Rh2 in yeast has recently been investigated as an alternative strategy compared to extraction from plants. However, the titer was quite low due to low catalytic capability of the key ginseng glycosyltransferase in microorganisms. Herein, we have demonstrated high-level production of ginsenoside Rh2 in Saccharomyces cerevisiae via repurposing an inherently promiscuous glycosyltransferase, UGT51. The semi-rationally designed UGT51 presented an ~1800-fold enhanced catalytic efficiency (kcat/Km) for converting protopanaxadiol to ginsenoside Rh2 in vitro. Introducing the mutant glycosyltransferase gene into yeast increased Rh2 production from 0.0032 to 0.39mg/g dry cell weight (DCW). Further metabolic engineering, including preventing Rh2 degradation and increasing UDP-glucose precursor supply, increased Rh2 production to 2.90mg/g DCW, which was more than 900-fold higher than the starting strain. Finally, fed-batch fermentation in a 5-L bioreactor led to production of ~300mg/L Rh2, which was the highest titer reported.

(+)-Meyeniins A-C, Novel Hexahydroimidazo[1,5-c]thiazole Derivatives from the Tubers of Lepidium meyenii: Complete Structural Elucidation by Biomimetic Synthesis and Racemic Crystallization.

(+)-Meyeniins A-C (1-3), a novel class of sulfur-containing hexahydroimidazo[1,5-c]thiazole derivatives, were isolated from the tubers of Lepidium meyenii (maca) cultivated in Lijiang, Yunnan province, China. Guided by their biosynthetic hypothesis, a stereocontrolled biomimetic synthesis of meyeniins A-C and their individual enantiomers was efficiently accomplished by a combination of a condensation reaction and Edman degradation. The formation of high-quality crystals for X-ray crystallography occurred much more readily from a racemic mixture of (±)-meyeniin A than with the single enantiomer alone in this case. These extensive strategies, combined with circular dichroism (CD) spectra, allowed the complete structural assignments of (+)-meyeniins A-C. Among them, (+)-meyeniin A showed moderate selective cytotoxicities against the HL-60, A549 and MCF-7 human cell lines with IC50 values of 14.41, 32.22, and 33.14 µM, respectively. To some extent, these findings support traditional applications of maca as healthy nutritional supplements or functional foods for cancer prevention.

Antiviral sesquiterpenes from leaves of Nicotiana tabacum.

Three unreported sesquiterpenes possessing two new skeletons, tabasesquiterpenes A-C (1-3), together with three known sesquiterpenes (3-6) were isolated from the leaves of Nicotiana tabacum. Their structures were determined mainly by spectroscopic methods, including extensive 1D- and 2D-NMR techniques. Compounds 1-6 were evaluated for their anti-tobacco mosaic virus (anti-TMV) activities. The results showed that compound 2 exhibited high anti-TMV activity with inhibition rate of 35.2%, which were higher than that of positive control (ningnanmycin). The other compounds also showed potential anti-TMV activity with inhibition rates in the range of 20.5-28.6%.

Anti-TMV activity flavones from the leaves of Yunnan local air cured tobacco.

Four new flavones, tobaflavones E-H (1-4), together with two known flavones (5 and 6), were isolated from the leaves of Dali Tiandeng tobacco (a variety of Yunnan local air cured tobacco). Their structures were elucidated by spectroscopic methods, including extensive 1D- and 2D NMR techniques. Compound 2 is the first naturally occurring flavone bearing a (4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)methyl moiety. These compounds were also evaluated for their anti-tobacco mosaic virus (anti-TMV) activity. The results revealed that compounds 1 and 2 exhibited high anti-TMV activity with inhibition rate of 35.3% and 39.6%, respectively. The rates are higher than those of positive control. The other compounds also showed potential anti-TMV activity with inhibition rates in the range of 18.7-28.4%, respectively.

Icetexane diterpenoids from Perovskia atriplicifolia.

Five new icetexane diterpenoids, namely, perovskatones B-D (1, 3, 4), 1α-hydroxybrussonol (2), and 1α-hydroxypisiferanol (5), were isolated from Perovskia atriplicifolia, together with a new natural product (6) and two known compounds, przewalskin E (7) and brussonol (8). The structures of the new compounds were elucidated by detailed analyses of their MS, IR, 1D, and 2D NMR data. Compounds 1-8 were assayed for their inhibitory hepatitis B virus activities in the HepG 2.2.15 cell line. The results suggested that compounds 1 and 2 possessed noticeable anti-hepatitis B virus activity in vitro, suppressing the replication of hepatitis B virus DNA with selectivity index values of 154.3 and 137.7, respectively.

Biphenyls from Nicotiana tabacum and their anti-tobacco mosaic virus.

Five new biphenyls, tababiphenyls A-E (1-5), together with five known ones (5-10), were isolated from the leaves of Nicotiana tabacum, of which compound 1 possessed a seldom reported 6-carbons unit in biphenyls. Their structures were established on the basis of extensive spectroscopic analyses. All compounds were tested for their anti-tobacco mosaic virus (anti-TMV) activities. The results showed that compounds 3 and 5 exhibited high anti-TMV activities with inhibition rate of 48.4% and 32.1%, respectively, which were higher than that of positive control (ningnanmycin). The other compounds also showed potential anti-TMV activities with inhibition rates in the range of 18.6-28.7%, respectively.

Cytotoxic oxepinochromenone and flavonoids from the flower buds of Rosa rugosa.

A new oxepinochromenone, rugosachromenone A (1), seven new flavonoids, rugosaflavonoids A-G (2-8), and 11 known compounds (9-19) were isolated from the flower buds of Rosa rugosa. Compound 1 is found from Nature for the first time. Compound 2 displayed cytotoxicity against NB4, SHSY5Y, and MCF7 cells with IC50 values of 2.2, 2.5, and 2.3 µM, respectively, and 3 was toxic to A549 and MCF7 cells with IC50 values of 1.2 and 2.8 µM, respectively.

Cytotoxic deoxybenzoins and diphenylethylenes from Arundina graminifolia.

Eight new C-4-alkylated deoxybenzoins (1-8), three new diphenylethylenes (9-11), and five known diphenylethylenes were isolated from Arundina graminifolia. The structures of 1-11 were elucidated by spectroscopic methods including extensive 1D and 2D NMR techniques. Compounds 9-11 are the first naturally occurring diphenylethylenes possessing a hydroxyethyl unit. Compounds 1-11 were evaluated for cytotoxicity against five human tumor cell lines. Compounds 4, 5, and 9-11 showed significant cytotoxicity against five cancer cell lines, with IC50 values ranging from 1.8 to 8.7 µM.