Bioactive solanidane steroidal alkaloids from Solanum lyratum.

Six previously unreported solanidane steroidal alkaloids, namely lyrasolanosides A-F, were isolated from Solanum lyratum. In addition, five known steroidal alkaloids were also identified. The structures of these compounds were determined through the use of NMR, HRESIMS,UV, IR and ECD analysis. To assess their bioactivities, the cytotoxic effects of the six previously unreported compounds were evaluated on A549 cells. The results revealed that lyrasolanoside B (2) exhibited the highest potency among them. Lyrasolanoside B (2) exhibited significant inhibition of cell migration, invasion, and adhesion dramatically. Mechanistically, it was found to suppress the activity of JAK2/STAT3 signaling pathway by downregulating the expression of phosphorylated JAK2/STAT3 in an exosome-dependent manner. In addition, lyrasolanoside B (2) was found to significantly upregulate the expression of E-cadherin and downregulate the expression of N-cadherin and vimentin. These findings indicate that lyrasolanoside B (2) inhibits the metastasis of A549 cells by suppressing exosome-mediated EMT. These findings suggest that lyrasolanoside B (2) may inhibit the metastasis of lung cancer by regulating A549-derived exosomes.

Xianglian Pill combined with 5-fluorouracil enhances antitumor activity and reduces gastrointestinal toxicity in gastric cancer by regulating the p38 MAPK/NF-κB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Perioperative or postoperative adjuvant chemotherapy based on 5-fluorouracil (5-FU) is a common first-line adjuvant therapy for gastric cancer (GC). However, drug resistance and the side effects of 5-FU have reduced its efficacy. Among these side effects, gastrointestinal (GI) toxicity is one of the most common. Xianglian Pill (XLP) is a Chinese patent medicine that is commonly used for the treatment of diarrhoea. It can reduce inflammation and has a protective effect on the intestinal mucosa. Recent studies have shown that many components of XLP can inhibite tumor cell growth. However, the therapeutic effect of XLP in combination with 5-FU on GC is unclear. AIM OF THE STUDY: To investigate whether the combination of XLP and 5-FU can enhance anti-GC activity while reducing GI toxicity. MATERIALS AND METHODS: XLP was administered orally during intraperitoneal injection of 5-FU in GC mice model. Mice were continuously monitored for diarrhea and xenograft tumor growth. After 2 weeks, the mice were sacrificed and serum was collected to determine interleukin-6 levels. Pathological changes, the expression of pro-inflammatory factors and p38 mitogen-activated protein kinase (MAPK) in GI tissue were determined by Western blot analysis. Pathological changes, apoptosis levels and p38 MAPK expression levels in xenograft tissues were also determined. RESULTS: The results showed that XLP could alleviate GI mucosal injury caused by 5-FU, alleviated diarrhea, and inhibited the expression of nuclear factor (NF)-κB and myeloid differentiation primary response-88. Besides, XLP could promote the 5-FU-induced apoptosis of GC cells and enhance the inhibitory effect of 5-FU on tumor xenografts. Further study showed that XLP administration could regulate the expression of p38 MAPK. CONCLUSIONS: XLP in combination with 5-FU could alleviate its GI side effects and enhance its inhibitory effect on xenograft tumor. Moreover, these effects were found to be related to the regulation of the p38 MAPK/NF-κB pathway.

Derivation of an induced pluripotent stem cell line (FDCHi014-A) from PBMCs of a seven-year-old patient with a truncating NOVA2 variant (c.625del).

Neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities (NEDASB) is a rare autosomal dominant disorder caused by a heterozygous mutation in the NOVA2 gene on chromosome 19q13. Here, we describe the generation and characterization of an iPSC line derived from the peripheral blood of a 7-year-old patient carrying a novel heterozygous mutation in NOVA2 (c.625 del). The iPSCs with the confirmed patient-specific mutation were demonstrated by pluripotency markers, a normal karyotype, and the ability to differentiate into three germ layers. This NOVA2-mutant iPSC line could facilitate disease modeling and therapy development studies for NEDASB.

In-hospital mortality and length of hospital stay in infants requiring tracheostomy with bronchopulmonary dysplasia.

PURPOSE: To investigate in-hospital mortality and hospital length of stay (LOS) in infants requiring tracheostomy with bronchopulmonary dysplasia (BPD). METHODS: We explored the correlation between tracheostomy with in-hospital mortality and LOS in infant patients hospitalized with BPD, using the data from Nationwide Inpatient Sample between 2008 and 2017 in the United States. In-hospital mortality and LOS was compared in patients who underwent tracheostomy with those patients who did not after propensity-score matching. RESULTS: A total of 10,262 children ≤2 years old hospitalized with BPD, 847 (8%) underwent tracheostomy, and 821 patients underwent tracheostomy were matched with 1602 patients without tracheostomy. Tracheostomy group was correlated with higher in-hospital mortality(OR(95%CI):2.98(2.25-3.95)) and prolonged LOS(absolute difference(95%CI):97.0(85.6-108.4)). CONCLUSIONS: Tracheostomy was correlated with increased in-hospital mortality and prolonged LOS. Such information may contribute to better decision-making process between clinicians and parents regarding tracheostomy to manage parent expectations, as well as better interdisciplinary teamwork.

Effect of mono- and diketone group in curcumin analogues on amyloid fibrillation of hen egg white lysozyme.

Curcumin has attracted more attention because of its inhibition efficacy on protein amyloid fibrillation. However, the inhibition mechanism was still ambiguous and the clinical application of curcumin was greatly limited because of its poor stability at physiological conditions for the presence of ß-diketone moiety. In this paper, a new mono-ketone-containing curcumin analogue (MDHC) was designed and synthesized to realize the possible inhibition mechanism and unveil the important role of ß-diketone moiety of curcumin in the inhibition process of amyloid fibrillation using hen egg white lysozyme (HEWL) as model protein. Although all experiment results (ThT, CR, ANS and TEM) showed that the inhibitory capacity of curcumin was better than MDHC, MDHC still could show obvious inhibition effect. Molecular docking showed that both curcumin and MDHC could bind with HEWL by hydrogen bond of phenloic hydroxyl and the binding energy of MDHC was higher than that of curcumin. All the findings inferred that ß-diketone group was one of great important groups in the inhibition process of HEWL amyloid fibrillation, which provided more room to construct novel inhibition reagents.

Aptamer Inhibits Tumor Growth by Leveraging Cellular Proteasomal Degradation System to Degrade c-Met in Mice.

Current action mechanisms for aptamer-based therapeutics depend on occupancy-driven pharmacology to mediate protein functions. We report a new mechanism where aptamers leverage cellular proteasomal degradation system to degrade proteins for cancer treatment. A DNA aptamer (hereinafter referred to as c-Met-Ap) binds to the extracellular domain of mesenchymal-epithelial transition factor (c-Met) and selectively induces c-Met phosphorylation at Y1003 and Y1349. The phosphorylation of Y1003 recruits E3 ubiquitin ligase casitas B-lineage lymphoma, causing c-Met ubiquitination and degradation in the proteasome. Furthermore, c-Met-Ap can induce a decrease in the heterodimeric partner proteins of c-Met and the downstream effector proteins in the c-Met signal axis, effectively inhibiting tumor growth in A549 tumor-bearing BALB/c mice. Our study uncovers a novel, actionable mechanism for aptamer therapeutics and opens a new avenue for developing highly efficient anticancer drugs.

A photochemically covalent lock stabilizes aptamer conformation and strengthens its performance for biomedicine.

Aptamers' vast conformation ensemble consisting of interconverting substates severely impairs their performance and applications in biomedicine. Therefore, developing new chemistries stabilizing aptamer conformation and exploring the conformation-performance relationship are highly desired. Herein, we developed an 8-methoxypsoralen-based photochemically covalent lock to stabilize aptamer conformation via crosslinking the inter-stranded thymine nucleotides at TpA sites. Systematical studies and molecular dynamics simulations were performed to explore the conformation-performance relationship of aptamers, revealing that conformation-stabilized aptamers displayed better ability to bind targets, adapt to physiological environment, resist macrophage uptake, prolong circulation half-life, accumulate in and penetrate into tumor than their counterparts. As expected, conformation-stabilized aptamers efficiently improved the therapeutic efficacy of aptamer-drug conjugation on tumor-bearing mice. Collectively, our study has developed a general, simple and economic strategy to stabilize aptamer conformation and shed light on the conformation-performance relationship of aptamers, laying a basis for promoting their basic researches and applications in biomedicine.

NMR-based metabolomic approach to understanding Zeng-Sheng-Ping-induced hepatotoxicity, and identifying possible toxic constituents by LC-MS profiles.

Zeng-Sheng-Ping (ZSP) tablets, made from six Chinese herbs, are widely used in the chemoprevention and treatment of precancerous lesions in patients with gastrointestinal cancer. However, sporadic cases of liver injury have occurred. Herein, the serum metabolites in hamsters with ZSP-induced liver damage were analyzed by NMR-based metabolomics. Twelve metabolites associated with ZSP-induced hepatoxicity were identified. Amino acid metabolism and the urea cycle were significantly altered, and three associated amino acid metabolic enzymes (PAH, GS, and GLS) were further validated by ELISA. Therefore, 12 metabolites and 3 amino acid metabolic enzymes were proposed as potential biomarkers in ZSP-induced liver injury. The chemical constituents of ZSP tablets were profiled using liquid chromatography-mass spectrometry. The furanoids in two herbs, Dioscorea bulbifera L. and Dictamnus dasycarpus Turcz., were proposed to be the major hepatotoxic constituents in ZSP, leading to an improved preparation method with low hepatotoxicity for ZSP.

Isorhamnetin: A review of pharmacological effects.

Isorhamnetin is one of the most important active ingredients in the fruits of Hippophae rhamnoides L. and the leaves of Ginkgo biloba L., which possesses extensive pharmacological activities. At present, there have been numerous investigations on isorhamnetin, which has the effects of cardiovascular and cerebrovascular protection, anti-tumor, anti-inflammatory, anti-oxidation, organ protection, prevention of obesity, etc. The related mechanisms involve the regulation of PI3K/AKT/PKB, NF-κB, MAPK and other signaling pathways as well as the expression of related cytokines and kinases. Isorhamnetin has a high value of development and application. However, the investigations on its mechanism of action are limited and lack of detailed scientific validation. The manuscript reviewed the pharmacological effects of isorhamnetin and related mechanisms of action for the development of its medicinal properties further.

Chemopreventive effect of modified zengshengping on oral cancer in a hamster model and assessment of its effect on liver.

Ethnopharmacological relevance Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors, seriously compromising patients' quality of life. Previous studies showed that Zengshengping (ZSP), a popular traditional Chinese medicine, has certain inhibiting effects on both oral precancerous lesions and OSCC. However, few reports underlined ZSP side effects such as liver toxicity, which limit its long-term application. Aim of the study was to evaluate the chemopreventive effect of a modified ZSPs formula on oral cancer in a hamster model. Its effect on hamster liver was also assessed. Materials and Methods The original medicine (ZSP-1) and other two formulas slightly different and called ZSP-2 and ZSP-3 were prepared ahead of time. DMBA (0.5%) was topically applied for 6 weeks to induce a premalignant lesion on hamsters' cheek pouch, then ZSP-1/2/3 were intragastrically administered for 8 weeks. Hamster treated with DMBA + each of the ZSPs represented the ZSP-1/2/3 groups, while those without ZSP-1/2/3 treatment represented the DMBA group. To assess the effect of ZSPs in the liver, intragastric administration of ZSP-1/2/3 was carried out to other groups of hamsters for 12 weeks and the blood was collected every two weeks to detect the hepatic function. Some of the hamsters were sacrificed at the end of 12 weeks, while the remaining animals were sacrificed after other 4 weeks to estimate the effect of ZSP-1/2/3 withdrawal on the liver. Results showed that tumor development in the ZSP-1/2/3 groups was less than that in DMBA group. BrdU, CD31 and COX-2 expression in the hyperplastic tissues was significantly lower in the ZSP-1/2/3 groups than that in the DMBA group. In addition, VEGF and COX-2 expression in ZSP-1/2/3 groups was lower while caspase-9 and p53 expression was higher than those in the DMBA group. Finally, PTEN expression in ZSP-1/2/3 groups was higher than that in the DMBA group. As regard the effect in the liver, ALP in the ZSP-1/2/3 groups was higher than that in the control group treated with an intragastric administration of ddH2O. After 4 weeks of withdrawal, the hamsters of the ZSP-3 group did not recover from the increase in ALP. Histopathology showed the presence of inflammatory lesions in each group after 12 weeks, especially in the ZSP-1/3 groups, and the number of apoptotic cells in the ZSP-3 group was higher than that in the other groups, without any recovery after withdrawal of the drug. At 12 weeks, the MDA in the ZSP-1 group was higher than that in the control group and the ZSP-2 group, but the difference disappeared after drug withdrawal because the MDA in the ZSP-1/3 groups decreased. Conclusions ZSP-2 possessed a chemopreventive effect against oral cancer by inhibiting inflammation, proliferation of tumor cells, generation of microvessels and by promoting tumor cell apoptosis. In addition, hepatotoxicity of ZSP-2, which might be related to oxidative stress injury, was reduced to some extent.

Scutellaria barbata: A Review on Chemical Constituents, Pharmacological Activities and Clinical Applications.

Scutellaria barbata has a long history of medical use in Traditional Chinese Medicine for removing heat and toxic material, promoting blood circulation and removing blood stasis, and inducing diuresis to reduce edema. Recent pharmacology investigations have provided evidence for its anti-cancer, bacteriostasis, anti-virus, anti-inflammation, anti-oxidation and immunity enhancement properties. The efficacy of activating blood circulation and removing blood stasis has unique advantages in the treatment of cardiovascular and cerebrovascular diseases. A total of 84 compounds have been isolated from S. barbata and are characterized mainly as flavonoids, diterpenoids, followed by polysaccharide, volatile oil and steroids. Peer-reviewed articles published over the last few years were gathered by consulting the databases PubMed, Elsevier, Springer, and Chinese Herbal Classics. This review mainly focuses on the pharmacologically active constituents isolated from S. barbata，which have been subjected to in vitro and/or in vivo studies. Although, the chemical components, pharmacological activities, toxicology, clinical applications and mechanisms of action of S. barbata have been investigated, many constituents remain unknown. Further investigations are required to investigate the medicinal properties of S. barbata.

[Studies on active aromatic constituents from rhizomes of Sophora tonkinensis].

Aromatic constituents from rhizomes of Sophora tonkinensis were purified by extensive chromatographic techniques including column chromatography over macroporous resin,MCI,silica gel,weak acid cation exchange resin,Sephadex LH-20,ODS,and semi-preparative HPLC. Twelve aromatic compounds were isolated and identified from the water aqueous extract of the rhizomes of S.tonkinensis. Their structures were elucidated as 4-( 3-hydroxypropyl) phenol( 1),( ±)-4-( 2-hydroxypropyl) phenol( 2),benzamide( 3),( ±)-3-( p-methoxyphenyl)-1,2-propanediol( 4),4-methoxybenzamide( 5),3-hydroxy-1-( 4-hydroxy-3-methoxyphenyl) propan-1-one( 6),tyrosol( 7),( ±)-2,3-dihydroxypropyl benzoate( 8),vanillin alcohol( 9),7,3'-dihydroxy-8,4'-dimethoxyisoflavone( 10),7,4'-dihydroxy-3'-methoxyisoflavone( 11),and 7,3'-dihydroxy-5'-methoxyisoflavone( 12). Compounds 1-9 were firstly isolated from the Sophora genus. Compounds 4,5,10 and 11 can remarkably protect Hep G2 cell against APAP-induced damage at the concentration of 10 µmol·L-1. Compounds 1-12 exhibited no significant activities on the assays of inhibition of LPS-induced NO production in RAW cell lines and NF-κB inhibition.

Phytochemistry, Pharmacological Activities, Toxicity and Clinical Application of Momordica cochinchinensis.

Momordica cochinchinensis (Lour.) Spreng (M. cochinchinensis) is a deciduous vine that grows in Southeast Asia. It is known as gac in Vietnam and as Red Melon in English. Gac is reputed to be extremely benificial for health and has been widely used as food and folk medicine in Southeast Asia. In China, the seed of M. cochinchinensis (Chinese name: Mu biezi) is used as traditional Chinese medicine (TCM) for the treatment of various diseases. More than 60 chemical constituents have been isolated from M. cochinchinensis. Modern pharmacological studies and clinical practice demonstrate that some chemical constituents of M. cochinchinensis possess wide pharmacological activities, such as anti-tumor, anti-oxidation, anti-inflammatory, etc. This paper reviews the phytochemistry, pharmacological activities, toxicity, and clinical application of M. cochinchinensis, aiming to bring new insights into further research and application of this ancient herb.

Prunella vulgaris: A Comprehensive Review of Chemical Constituents, Pharmacological Effects and Clinical Applications.

Prunella vulgaris (PV) is a perennial herb belonging to the Labiate family and is widely distributed in the northeastern Asian countries such as Korea, Japan, and China. It is reported to display diverse biological activities including anti-microbial, anti-cancer, and anti-inflammation as determined by in vitro or in vivo studies. So far, about 200 compounds have been isolated from PV plant and a majority of these have been characterized mainly as triterpenoids, sterols and flavonoids, followed by coumarins, phenylpropanoids, polysaccharides and volatile oils. This review summarizes and analyzes the current knowledge on the chemical constituents, pharmacological activities, mechanisms of action and clinical applications of the PV plant including its potential as a future medicinal plant. Although some of the chemical constituents of the PV plant and their mechanisms of action have been investigated, the biological activities of many of these remain unknown and further clinical trials are required to further enhance its reputation as a medicinal plant.

Bioactive phenolic acid-substituted glycoses and glycosides from rhizomes of Cibotium barometz.

Two rarely phenolic acid-substituted alloses (1, 2) and one new glucoside (3), as well as nine known compounds (4-12) were isolated from rhizomes of Cibotium barometz (L.) J. Sm. Structures of 1-3 were established by extensively spectroscopic analyses (NMR, MS, etc.) and acid hydrolysis. All compounds were evaluated for the hepatoprotective activities against APAP-induced HepG2 cell damage. Compounds 1, 4-7, 10 exhibited significant hepatoprotective activities, even more strongly than positive control, bicycol. In addition, compounds 1 and 9 could reduce PC12 cell death induced by serum deprivation.

Metabolomic analysis of raw Pinelliae Rhizoma and its alum-processed products via UPLC-MS and their cytotoxicity.

Alum-processing is a traditional method to attenuate the toxicity of Pinelliae Rhizoma (tubers of Pinellia ternate, PT). The present study aimed at investigating the chemical and cytotoxic changes during alum processing. Metabolomic profiles of raw and alum-processed PT were studied based on ultra-performance liquid chromatography coupled with Orbitrap mass spectrometry. More than 80 chemicals in positive MS mode and 40 chemicals in negative MS mode, such as organic acids, amino acids, glucosides and nucleosides, were identified after multivariate statistical analysis, including principal component analysis and orthogonal partial least-square discriminant analysis. Almost all of the identified chemical markers were significantly decreased ~10- to 100-fold after alum processing. Meanwhile, the correlations between the chemical markers were assimilated to a positive coefficient from disorderly distribution during the processing. Raw PT extracts could inhibit the proliferation of human carcinoma cells (HCT-116, HepG2, and A549) at the rate of 40.5, 24.8 and 31.6% more strongly than processed PT. It was concluded that the alum processing of PT could decrease the number of actively water-soluble principles at the same time as decreasing toxicity. Given the water-insoluble property of toxic calcium oxalate raphides in PT, we suggest that a more scientific processing method should be sought.

New path to treating pancreatic cancer: TRAIL gene delivery targeting the fibroblast-enriched tumor microenvironment.

Gene therapy has shown promise in antitumor strategies for advanced cancer. However, efficient and safe delivery of potent therapeutic gene expressing in specific tumor tissues remains elusive, especially when there exist stromal obstacles. Here we report a non-viral gene delivery approach targeting pancreatic stellate cells (PSCs) as the transfection host in the fibroblast-enriched tumor microenvironment of pancreatic cancer. Plasmid DNA (pDNA) encapsulated in branched polyethylenemine (BPEI) was found to selectively transfect PSCs rather than pancreatic cancer cells and other fibroblast cell lines. Mechanism investigations reveal that the highly expressed fibroblast growth factor receptors (FGFRs) in PSCs facilitated the cellular uptake of polyplexes in PSCs. This delivery platform carrying gene encoding of TNF-related apoptosis-inducing ligand (TRAIL) displayed effective by-stander effect and tumor cell-selective cytotoxicity. More importantly, the therapeutic efficacy was proved in a PSC-enriched orthotopic pancreatic tumor model. Thus, this gene delivery strategy smartly converts PSCs as the microenvironment obstacle for drug delivery into the producer and reservoir of selective tumor-killing proteins.

Saikosaponins: a review of pharmacological effects.

Over the past decades, a number of phytochemicals have been reported to possess potent pharmacological effects. Saikosaponins represent a group of oleanane derivatives, usually as glucosides, which are commonly found in medicinal plants Bupleurum spp., which have been used as traditional Chinese medicine for more than 1,000 years in China. Emerging evidence suggests that saikosaponins have many pharmacological effects, including sedation, anticonvulsant, antipyretic, antiviral, immunity, anti-inflammation, antitumor properties, protecting liver and kidney and so on. The present review provides a comprehensive summary and analysis of the pharmacological properties of saikosaponins, supporting the potential uses of saikosaponins as a medicinal agent.

[A new styrene dimer derivative from Litsea greenmaniana].

A new styrene dimer derivative has been isolated from the branch of Litsea greenmaniana by column chromatography over silica gel and Sephadex LH-20, as well as semi-preparative HPLC. Its structure was identified by spectroscopic data analysis (MS, UV, IR, 1D and 2D NMR) as (E)-2,4-bis(p-hydroxyphenyl)-2-butenol, named as listeanol. At a concentration of 1×10-5 mol•L⁻¹, compound 1 was inactive in the assays, including cytotoxicity against human tumor cell lines (HCT-8, Bel-7402, BGC-823, A549 and A2780), antioxidant activity in Fe²âº-cystine-induced rat liver microsomal lipid peroxidation, neuroprotective activity against serum deprivation or glutamate induced neurotoxicity in cultures of PC12 cells, and the inhibitory activity against protein tyrosine phosphatase 1B (PTP1B).