Corynoline inhibits esophageal squamous cell carcinoma growth via targeting Pim-3.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is an aggressive and deadly malignancy characterized by late-stage diagnosis, therapy resistance, and a poor 5-year survival rate. Finding novel therapeutic targets and their inhibitors for ESCC prevention and therapy is urgently needed. METHODS: We investigated the proviral integration site for maloney murine leukemia virus 3 (Pim-3) protein levels using immunohistochemistry. Using Methyl Thiazolyl Tetrazolium and clone formation assay, we verified the function of Pim-3 in cell proliferation. The binding and inhibition of Pim-3 by corynoline were verified by computer docking, pull-down assay, cellular thermal shift assay, and kinase assay. Cell proliferation, Western blot, and a patient-derived xenograft tumor model were performed to elucidate the mechanism of corynoline inhibiting ESCC growth. RESULTS: Pim-3 was highly expressed in ESCC and played an oncogenic role. The augmentation of Pim-3 enhanced cell proliferation and tumor development by phosphorylating mitogen-activated protein kinase 1 (MAPK1) at T185 and Y187. The deletion of Pim-3 induced apoptosis with upregulated cleaved caspase-9 and lower Bcl2 associated agonist of cell death (BAD) phosphorylation at S112. Additionally, binding assays demonstrated corynoline directly bound with Pim-3, inhibiting its activity, and suppressing ESCC growth. CONCLUSIONS: Our findings suggest that Pim-3 promotes ESCC progression. Corynoline inhibits ESCC progression through targeting Pim-3.

Impacts and mechanisms of alternative mRNA splicing in cancer metabolism, immune response, and therapeutics.

Alternative pre-mRNA splicing (AS) provides the potential to produce diversity at RNA and protein levels. Disruptions in the regulation of pre-mRNA splicing can lead to diseases. With the development of transcriptome and genome sequencing technology, increasing diseases have been identified to be associated with abnormal splicing of mRNAs. In tumors, abnormal alternative splicing frequently plays critical roles in cancer pathogenesis and may be considered as new biomarkers and therapeutic targets for cancer intervention. Metabolic abnormalities and immune disorders are important hallmarks of cancer. AS produces multiple different isoforms and diversifies protein expression, which is utilized by the immune and metabolic reprogramming systems to expand gene functions. The abnormal splicing events contributed to tumor progression, partially due to effects on immune response and metabolic reprogramming. Herein, we reviewed the vital role of alternative splicing in regulating cancer metabolism and immune response. We discussed how alternative splicing regulates metabolic reprogramming of cancer cells and antitumor immune response, and the possible strategies to targeting alternative splicing pathways or splicing-regulated metabolic pathway in the context of anticancer immunotherapy. Further, we highlighted the challenges and discuss the perspectives for RNA-based strategies for the treatment of cancer with abnormally alternative splicing isoforms.

[Bibenzyls from Dendrobium officinale].

Fifteen bibenzyls were isolated and purified from the ethyl acetate extract of the stems of Dendrobium officinale by macroporous resin, MCI, silica gel, Sephadex LH-20, and ODS column chromatographies, as well as preparative thin-layer chromatography and preparative HPLC. The structures of compounds were identified according to the spectra data of ~1H-NMR, ~(13)C-NMR, and MS, and the physical and physiochemical properties: dendrocandin X(1), 3,4'-dihydroxy-4,5-dimethoxybibenzyl(2), 6″-de-O-methyldendrofindlaphenol A(3), 3,4-dihydroxy-4',5-dimethoxybibenzyl(4), dendrosinen B(5), 3,4,4'-trihydroxy-5-methoxybibenzyl(6), 3,3'-dihydroxy-4,5-dimethoxybibenzyl(7), 3,4'-dihydroxy-5-methoxybibenzyl(8), moscatilin(9), gigantol(10), 4,4'-dihydroxy-3,5-dimethoxybibenzyl(11), 3,4',5-trihydroxy-3'-methoxybibenzyl(12), 3-O-methylgigantol(13), dendrocandin U(14), and dendrocandin N(15). Compound 1 was a novel compound. Compound 2 was isolated from Dendrobium species for the first time. Compounds 3-7 were isolated from D. officinale for the first time.

Contrasting results of tests of peripheral vestibular function in patients with bilateral large vestibular aqueduct syndrome.

OBJECTIVE: To analyze and summarize the effect of bilateral large vestibular aqueducts in peripheral vestibular organ function. METHODS: Eighteen patients with bilateral large vestibular aqueduct syndrome (LVAS; Study Group) and 18 healthy volunteers (Control Group) were investigated using audiometry, caloric test, sensory organization test (SOT), and vestibular-evoked myogenic potential (VEMP) tests. RESULTS: All 18 patients (36 ears) exhibited sensorineural hearing loss. For cervical VEMP (cVEMP), the Study Group showed lower thresholds (Study Group vs. CONTROL GROUP: 71.4vs. 75.3dBnHL; p=0.006), N1 latencies (24.1vs. 25.2ms; p=0.026) and shorter P1 (15.3vs. 16.6ms; p=0.003), and higher amplitudes (400.7vs. 247.2µV; p<0.001) than the Control Group. For ocular VEMP (oVEMP), the Study Group had lower thresholds (79.3vs. 81.8dBnHL; p=0.046) and higher amplitudes (40.6vs. 14.4µV; p<0.001) than the Control Group. Fourteen of 16 patients (87.5%) who completed caloric tests had abnormal results, and 10 of 18 patients (55.6%) exhibited abnormal results in SOTs. CONCLUSIONS: The hyperfunction of vestibular test in otolithic organs and the hypofunction of vestibular test in semicircular canals, as well as the dysfunction in the balance test were demonstrated in patients with LVAS. SIGNIFICANCE: Our findings can help clinicians gain a better understanding of the characteristics of vestibular organ function in patients with LVAS, which can facilitate optimal targeted treatment.

Cloning and identification of a YY-1 homolog as a potential transcription factor from Pinctada fucata.

Biomineralization is an important and ubiquitous process in organisms. The shell formation of mollusks is a typical biomineral physical activity and is used as a canonical model in biomineralization research. Most recent studies focused on the identification of matrix proteins involved in shell formation; however, little is known about their transcriptional regulation mechanism, especially the transcription factors involved in shell formation. In this study, we identified a homolog of the YY-1 transcriptional factor from Pinctada fucata, named Pf-YY-1, and characterized its expression pattern and biological functions. Pf-YY-1 has a typical zinc finger motif highly similar to those in humans, mice, and other higher organisms, which indicated its DNA-binding capability and its function as a transcription factor. Pf-YY-1 is ubiquitously expressed in many tissues, but at a higher level in the mantle, which suggested a role in biomineralization. The expression pattern of Pf-YY-1 during pearl sac development was quite similar to, and was synchronized with, those of Prisilkin-39, ACCBP, and other genes involved in biomineralization, which also suggested its function in biomineralization.

Renal protective effect of Rosa laevigata Michx. by the inhibition of oxidative stress in streptozotocin-induced diabetic rats.

Diabetic nephropathy (DN) is a long-term complication of diabetic mellitus. Numerous reports have suggested that oxidative stress is defined as the excessive production of reactive oxygen species (ROS) surpassing existing anti-oxidative defense mechanisms, and plays a critical role in the pathogenesis of diabetic nephropathy. Rosa laevigata Michx. (RLM) is the commonly used traditional Chinese medicine for the treatment of chronic urinary tract infections and anti-oxidative treatments, and has been shown to have a renal protective effect in diabetic rats. In the present study, we further investigate the effects of RLM on oxidative stress in the kidneys of streptozotocin-induced diabetic rats with DN. Our results suggest that RLM significantly ameliorates renal dysfunction in diabetic rats. The protection against the development of DN by RLM treatment involves increasing the activity of superoxide dismutase and total anti-oxidant capacity, decreasing the levels of malondialdehyde and ROS, and inhibiting the expression of nuclear factor-κB p65 and monocyte chemoattractant protein-1 at both the protein and mRNA levels with a concomitant increase in the expression of the IκBα protein. These results highlight the potential therapeutic application of RLM for the treatment of DN.

Anxiolytic and sedative activities of Passiflora edulis f. flavicarpa.

AIM OF THE STUDY: Many plants in the genus Passiflora have long been used in traditional folk medicines as a remedy for many neurogenic diseases in many countries. A number of species of the genus was studied about their neuropharmacological activities, but the results were inconsistent. No literature reported neuropharmacological studies on Passiflora edulis f. flavicarpa as yet. The present study was aimed at evaluating the anxiolytic and sedative activities of Passiflora edulis f. flavicarpa. MATERIALS AND METHODS: Swiss albino mice were used as experimental animals in elevated plus-maze (EPM) test and spontaneous activity (SA) test to assay the behavioral effects of ethanolic extract (EE) of the aerial part of Passiflora edulis f. flavicarpa and its fractions, viz. petrol ether extract (PEE), ethyl acetate extract (EAE), n-BuOH extract (BE) and aqueous extract (AE), together with subfractions of BE, viz. BEF-I, BEF-II, BEF-III, BEF-IV and isoorientin, a flavonoid component isolated from BEF-III. RESULTS: In the EPM test, single-dose oral administration of EE (300 mg/kg and 400mg/kg), BE (125 mg/kg and 200mg/kg), AE (200mg/kg and 300 mg/kg), BEF-I (200mg/kg), BEF-II (200mg/kg), BEF-III (100mg/kg), or isoorientin (20mg/kg) resulted in anxiolytic-like effects, but a sedative-like activity was produced at higher doses, such as 300 mg/kg of BE, 200mg/kg of BEF-III, or 40 mg/kg and 80 mg/kg of isoorientin. The results of the SA test manifested that treatment with 400mg/kg of EE, 300 mg/kg of BE, or 40 mg/kg and 80 mg/kg of isoorientin compromised motor activity in mice, which are in line with the results of the EPM test. CONCLUSIONS: The aerial part of Passiflora edulis f. flavicarpa was anxiolytic at low dose but sedative at high dose. Flavonoids are important active constituents. Since AE contained little flavonoids, it was conjectured that there were other components responsible for the anxiolytic effect of Passiflora edulis f. flavicarpa besides flavonoids.

[Studies on the chemical constituents of Passiflora edulis f. flavicarpa].

OBJECTIVE: To study the main chemical constituents of Passiflora edulis f. flavicarpa Degener. METHODS: Six compounds were separated from the stem of the title plant and their structures were elucidated by spectral analysis and chemical evidence. RESULTS: These compounds were identified as luteolin 6-C-beta-D-glucopyranoside (1), luteolin 6-C-beta-D-chinovoside (2), luteolin 6-C-beta-L-fucoside (3), apigenin 8-C-beta-D-glucopyranoside (4), apigenin-6-C-beta-D-glucopyrano-4'-O-alpha-L-rhamnopyranoside (5), 5,8-epidioxyergosta-6, 22-dien-3ol (6). CONCLUSION: Compound 5 is obtained from the genus of Passiflora for the first time, Compounds 1, 5, 6 are isolated from the plant for the first time.

[Update review of Passiflora].

Passiflora was a nourishing and healthy fruit grown in tropical and subtropical regions. Passiflora has been widely used to alleviate various diseases in the folk in tropical nations, especially as a treatment for insomnia and anxiety in Europe. The title plant had been used as antalgesic and downer from the beginning of the 20th century up to now. The demands of Passiflora and its extract have been increasing. Therefore, comprehensive utilization of this plant is necessary. This paper reviewed the progress in the study on the chemical composition, nutrient value, and pharmacological effect of the genus of Passiflora.

N40, a novel nonacidic matrix protein from pearl oyster nacre, facilitates nucleation of aragonite in vitro.

A novel nonacidic matrix protein from pearl oyster nacre has been purified by cation-exchange chromatography. It was designated N40 for the nacreous protein of approximately 40 kDa. On the basis of the extraction method (with Tris-buffered Milli-Q water) and amino acid compositions (Gly- and Ala-rich), N40 was inferred to be a conventional "insoluble matrix protein". Crystallization experiments showed that N40 could facilitate the nucleation of aragonite drastically. So far, among the macromolecules that have been purified from the shell, N40 is an exclusive protein that can nucleate aragonite by itself, without the need for adsorption to a substrate. Thus, the present study has proposed the possibility that the nonacidic shell protein (maybe a conventional "insoluble framework protein") can also directly participate in aragonite nucleation and even act as a nucleation site. It is a valuable supplement to the classic biomineralization theory, in which the soluble acidic proteins of the shell are generally believed to function as a nucleation site.