Anthracycline chemicals with anthracyclinone structure exert antitumor effects by inhibiting angiogenesis and lymphangiogenesis in a xenografted gastric tumor model.

BACKGROUND: It is vital to screen or develop alternative therapeutic drugs with higher curative characteristics and fewer side effects for the clinical treatment of gastric cancer. METHODS: Gastric cancer cells were exposed to different auramycin G doses while determining the impact on cell viability, migration, and invasion. Then the antitumor effects of auramycin G, 5-fluorouracil (5-Fu) and their combination were evaluated. Furthermore, the molecular mechanisms of angiogenesis and lymphangiogenesis regulated by auramycin G and its analogs were investigated. RESULTS: Auramycin G inhibited cell viability in a dose-dependent manner, with a 50% inhibitory concentration of 23.72 ± 6.36 mg/L and 32.54 ± 5.91 mg/L for AGS and MGC803 cells, respectively. The migration and invasion of gastric cancer cells were significantly inhibited by 10 mg/L auramycin G, which was consistent with the down-regulation of the VEGFR2-VEGFA-pPI3K-pAkt-pErk1 and VEGFR3-VEGFC-pPI3K-pAkt-pmTOR proteins. Notably, the average tumor weights were significantly reduced in both the auramycin G (2.21 ± 0.45 g) of 50 mg/kg body weight and auramycin G + 5-fluorouracil (5-Fu) groups (1.33 ± 0.28 g), compared with the control (3.73 ± 0.56 g). Considering that auramycin G decreased the growth of blood and lymphatic vessels while reducing the degree of tumor malignancy, it effectively suppressed tumors by regulating the angiogenic and lymphangiogenic pathways. CONCLUSION: The present study confirmed that auramycin G displayed a prominent antitumor activity in gastric tumor models, both in vitro and in vivo. Moreover, it was confirmed that auramycin G played a specific role in certain gastric cancer cell types, while the mechanism was validated to be associated with angiogenesis- and lymphangiogenesis-related pathway suppression.

Altered Functional Connectivity Strength at Rest in Medication-Free Obsessive-Compulsive Disorder.

Background: Previous studies explored the whole-brain functional connectome using the degree approach in patients with obsessive-compulsive disorder (OCD). However, whether the altered degree values can be used to discriminate OCD from healthy controls (HCs) remains unclear. Methods: A total of 40 medication-free patients with OCD and 38 HCs underwent a resting-state functional magnetic resonance imaging (rs-fMRI) scan. Data were analyzed with the degree approach and a support vector machine (SVM) classifier. Results: Patients with OCD showed increased degree values in the left thalamus and left cerebellum Crus I and decreased degree values in the left dorsolateral prefrontal cortex, right precuneus, and left postcentral gyrus. SVM classification analysis indicated that the increased degree value in the left thalamus is a marker of OCD, with an acceptable accuracy of 88.46%, sensitivity of 87.50%, and specificity of 89.47%. Conclusion: Altered degree values within and outside the cortical-striatal-thalamic-cortical (CSTC) circuit may cocontribute to the pathophysiology of OCD. Increased degree values of the left thalamus can be used as a future marker for OCD understanding-classification.

Decreased Nucleus Accumbens Connectivity at Rest in Medication-Free Patients with Obsessive-Compulsive Disorder.

Background: Patients with obsessive-compulsive disorder (OCD) experience deficiencies in reward processing. The investigation of the reward circuit and its essential connectivity may further clarify the pathogenesis of OCD. Methods: The current research was designed to analyze the nucleus accumbens (NAc) functional connectivity at rest in medicine-free patients with OCD. Forty medication-free patients and 38 gender-, education-, and age-matched healthy controls (HCs) were recruited for resting-state functional magnetic resonance imaging. Seed-based functional connectivity (FC) was used to analyze the data. LIBSVM (library for support vector machines) was designed to identify whether altered FC could be applied to differentiate OCD. Results: Patients with OCD showed remarkably decreased FC values between the left NAc and the bilateral orbitofrontal cortex (OFC) and bilateral medial prefrontal cortex (MPFC) and between the right NAc and the left OFC at rest in the reward circuit. Moreover, decreased left NAc-bilateral MPFC connectivity can be deemed as a potential biomarker to differentiate OCD from HCs with a sensitivity of 80.00% and a specificity of 76.32%. Conclusion: The current results emphasize the importance of the reward circuit in the pathogenesis of OCD.

Increased cerebellar-default-mode network connectivity at rest in obsessive-compulsive disorder.

Abnormalities of the cerebellum and default-mode network (DMN) in patients with obsessive-compulsive disorder (OCD) have been widely reported. However, alterations of reciprocal functional connections between the cerebellum and DMN at rest in OCD remain unclear. Forty patients with OCD and 38 gender-, age-, and education-matched healthy controls (HCs) underwent resting-state functional magnetic resonance imaging scan. Seed-based functional connectivity (FC) and support vector machine (SVM) were applied to analyze the imaging data. Compared with HCs, patients with OCD exhibited increased FCs between the left Crus I-left superior medial prefrontal cortex (MPFC) and between the right Crus I-left superior MPFC, left middle MPFC, and left middle temporal gyrus (MTG). A significantly negative correlation was observed between the right Crus I-left MTG connectivity and the Yale-Brown Obsessive-Compulsive Scale compulsion subscale scores in the OCD group (r = - 0.476, p = 0.002, Bonferroni corrected). SVM classification analysis indicated that a combination of the left Crus I-left superior MPFC connectivity and the right Crus I-left middle MPFC connectivity can be used to discriminate patients with OCD from HCs with a sensitivity of 85.00%, specificity of 68.42%, and accuracy of 76.92%. Our study highlights the contribution of the cerebellar-DMN connectivity in OCD pathophysiology and provides new findings to OCD research.

Heat-stress-induced metabolic changes and altered male reproductive function.

Heat stress can cause systemic physiological and biochemical alterations in living organisms. In reproductive systems, heat stress induces germ cell loss and poor quality semen. However, until now, little has been known about such a complex regulation process, particularly in the perspective of metabolism. In this study, serum, hypothalamus, and epididymis samples derived from male SD (Sprague-Dawley) rats being exposed to high environmental temperature (40 °C) 2 h per day for 7 consecutive days were analyzed using metabonomics strategies based on GC/TOFMS. Differentially expressed metabolites reveal that the energy metabolism, amino acid neurotransmitters, and monoamine neurotransmitters pathways are associated with heat stress, in accordance with changes of the three upstream neuroendocrine system pathways in the SNS (sympathetic adrenergic system), hypothalamic pituitary adrenal axis (HPA), and hypothalamic pituitary testis axis (HPT) axis. Many of these metabolites, especially in the epididymis, were found to be up-regulated, presumably due to a self-preserving action to resist the environmental hot irritation to maintain normal functioning of the male reproductive system.

A GSHS-like gene from Lycium chinense maybe regulated by cadmium-induced endogenous salicylic acid and overexpression of this gene enhances tolerance to cadmium stress in Arabidopsis.

KEY MESSAGE: A GSHS gene, LcGSHS , was cloned from L. chinense for the first time. Evidence is presented here that endogenous SA accumulation maybe important for the regulation of LcGSHS expression level. Glutathione (GSH) plays a pivotal role in heavy metal detoxification. GSH synthetase (GSHS) catalyzes the rate-limiting step of GSH synthesis in plants. Salicylic acid (SA) is one of the important plant hormones, which plays a critical role in triggering plant responses to different stresses such as cadmium (Cd) stress. Until now, little has been done to explore the relationship among the accumulation of endogenous SA, GSHS transcript levels and the GSH content in plants under Cd treatment and we will investigate this link in this study. The chlorophyll content, transcripts level of LcGSHS gene, endogenous SA accumulation, GSH accumulation and Cd concentration in the leaves of Lycium chinense were studied under different treatment conditions. Endogenous SA, LcGSHS transcript expression and GSH content can be induced by Cd treatment in L. chinense, however, reduced by co-treatment with 2-aminoindan-2-phosphonic acid (AIP), an inhibitor of SA biosynthesis. Strong staining was observed in the leaves of Arabidopsis expressing ProLcGSHS::GUS under Cd stress and the staining was reduced by co-treatment with AIP. The transgenic Arabidopsis expressing ProLcGSHS::LcGSHS also showed greater tolerance to Cd stress than wild types. Evidence was presented here that under Cd stress, GSH accumulation occurred via enhanced LcGSHS gene expression and the SA signaling cascade was involved in this accumulation. Furthermore, the overexpression of LcGSHS in transgenic Arabidopsis resulted in greater tolerance to Cd stress than wild-type lines.

The alleviative effects comparison of four flavonoids from bamboo leaves on ulcerative colitis in an Alzheimer mouse model.

BACKGROUND: Clinically, patients with dementia are at high risk of developing enteritis, especially those with AD. This study explored the potential therapeutic benefits of bamboo leaf flavonoids (BLF) for ulcerative colitis (UC) treatment in Alzheimer's disease (AD) mouse model. METHODS: Various methods were employed, including pathological staining of brain/colon tissue, inflammatory cytokine detection in serum, and oxidative stress indicator assessment to compare ulcerative enteritis (UC) injury in normal and AD mice and determine whether AD mice were susceptible to colitis. Then, the effects of BLF on UC and AD were investigated via several unique indices further to determine whether it alleviated colitis injury and possessed beneficial properties. Moreover, four main components of BLF were utilized to treat primary colon epithelial cells and neuron cells to compare their effects in alleviating inflammation and oxidation. Furthermore, homoorientin embedded with ursolic acid was detected by HPLC and the in vitro release simulation experiments of the nanoparticles were performed. RESULTS: BLF complexes positively impacted ulcerative colitis by reducing disease activity, it also helped to reduce inflammation. Moreover, the BLF complexes decreased oxidative stress in the brain and colon tissues, indicating its potential as a neuroprotective agent. The flavonoid complexes reduced the expression levels of GFAP, Iba-1, and Aß in the brain tissue, highlighting its role in attenuating neuroinflammation and AD pathology. Additionally, the embedded homoorientin coated with ursolic acid showed stronger bioactivities when compared with the uncoated group. CONCLUSION: These results suggest that BLF complexes and its four main chemicals may be useful for treating AD- and UC-related complications, the embedded homoorientin coated with ursolic acid even demonstrated stronger bioavailability than homoorientin. Considering BLF complexes were verified to suppress the progressions of AD and UC for the first time, and the embedded homoorientin was never reported in published articles, the present study might provide a new perspective on its potential applications.

Antiproliferative polycyclic polyprenylated acylphloroglucinols from Garcinia paucinervis.

Bioassay-guided isolation of the stems of Garcinia paucinervis led to one new adamantane-type polycyclic polyprenylated acylphloroglucinols (PPAPs), (-)-garpauvinin A (1), and four known analogues (2-5). The structure and absolute configuration of 1 was established via spectroscopic techniques and ECD method. All the isolates displayed moderate antiproliferative activity against HL-60, PC-3 and Caco-2 human cancer cell lines with IC50 values ranging from 0.81 to 19.92 µM, and exhibited low toxicity on WPMY-1 normal human cells, showing selectivity between normal and malignant prostate cells. The biosynthetic pathways of the isolated PPAPs were proposed.

Reduced functional connectivity of the right dorsolateral prefrontal cortex at rest in obsessive-compulsive disorder.

BACKGROUND: Neuroimaging studies have revealed the role of the right dorsolateral prefrontal cortex (DLPFC) in the neurobiological mechanism of obsessive-compulsive disorder (OCD). However, only a few studies have examined the functional connectivity (FC) pattern of the right DLPFC at rest in OCD. OBJECTIVE: The aim of this research is to examine the FC patterns of the right DLPFC at rest in OCD. METHODS: Twenty-eight medication-free patients with OCD and 20 healthy controls underwent resting-state functional magnetic resonance imaging. Seed-based FC and support vector machine (SVM) were used to analyze the imaging data. RESULTS: The patients with OCD showed reduced FC values in the right middle temporal gyrus (MTG), right superior temporal gyrus, right ventral anterior cingulate cortex (vACC), and left Crus II. No brain regions showed a remarkable difference in FC values in patients with OCD after 8 weeks of medication treatment. The reduced right DLPFC-right MTG and right DLPFC-right vACC connectivities were correlated with the clinical symptoms of OCD. SVM results showed that reduced right DLPFC-right MTG connectivity at rest could predict the therapeutic response to OCD medication. CONCLUSIONS: The findings highlight the important role of the right DLPFC in the pathophysiological mechanism of OCD.

Exploring the key factors of schizophrenia relapse by integrating LC-MS/1H NMR metabolomics and weighted correlation network analysis.

BACKGROUND: Lack of comprehending key factors of schizophrenia relapse has impeded its effective treatment, indicating that the mechanism clarification and available intervention of schizophrenia relapse required further amelioration. METHOD: Based on the integration of LC-MS and 1H NMR metabolomics, a weighted correlation network was established to screen pivotal factors of accelerating schizophrenia relapse. Then, the cluster most correlated with schizophrenia relapse was explored, and the biological function of cluster was investigated. Next, the key biomarker related to schizophrenia relapse was obtained through multiple algorithms. Moreover, the Lilikoi algorithm and correlation analysis were implemented to reveal the association between key biomarker and schizophrenia relapse. RESULT: Results showed that 458 different forms of metabolites were identified for structuring the weighted correlation network. The module-trait correlation indicated that the turquoise module was the most highly correlated with schizophrenia relapse. Further, network analysis revealed that, in turquoise module, cluster 1 composed of 139 metabolites (involved in lipid metabolism and energy metabolism) was the most important subnetwork relevant to schizophrenia relapse. Finally, phenylalanylphenylalanine was recommended as the key biomarker related to schizophrenia relapse. Moreover, the correlation analysis indicated that phenylalanylphenylalanine might affect the progression of schizophrenia by intervening in energy metabolism. CONCLUSION: In summary, critical factors of schizophrenia relapse have been revealed in our research, expounding the schizophrenia progression more systemically, which could shed some light on improving the intervention of schizophrenia relapse.

An integrated pathological research for precise diagnosis of schizophrenia combining LC-MS/1H NMR metabolomics and transcriptomics.

BACKGROUND: Lack of clinically specific biomarkers has impeded the precise diagnosis of schizophrenia, meanwhile, limited comprehending of pathogenesis for schizophrenia has restricted the effective treatment. METHOD: An integrated multi-omic approach, combining metabolomic platform (LC-MS and 1H NMR) and transcriptomic platform, was established to differentiate healthy subjects from schizophrenia patients. Based on filtered metabolites and genes, characteristic spectrums were further built. Then, representative metabolites and genes were screened out through Boruta algorithm. Moreover, characteristic diagnostic formulas were established via LASSO regression analysis. RESULT: As a result, 86 differential metabolites (in line with amino acid metabolism, etc.) and 189 differential expression genes (involving in amino acid metabolic process, etc.) were obtained as potential biomarkers for schizophrenia. The latent interaction between metabolites with genes, such as HMGCLL1 with energy metabolism, etc., was further studied through the analysis of pathway-based integration. Moreover, fine predictive ability was attributed to characteristic metabolomic/transcriptomic diagnostic spectrums/formulas. CONCLUSION: The functional relationships of filtered metabolites and genes were studied, which could elaborate the pathological process of schizophrenia more systemically, supplying more precise information on mechanism description and diagnostic evidence of schizophrenia.

Disrupted Asymmetry of Inter- and Intra-Hemispheric Functional Connectivity at Rest in Medication-Free Obsessive-Compulsive Disorder.

Disrupted functional asymmetry of cerebral hemispheres may be altered in patients with obsessive-compulsive disorder (OCD). However, little is known about whether anomalous brain asymmetries originate from inter- and/or intra-hemispheric functional connectivity (FC) at rest in OCD. In this study, resting-state functional magnetic resonance imaging was applied to 40 medication-free patients with OCD and 38 gender-, age-, and education-matched healthy controls (HCs). Data were analyzed using the parameter of asymmetry (PAS) and support vector machine methods. Patients with OCD showed significantly increased PAS in the left posterior cingulate cortex, left precentral gyrus/postcentral gyrus, and right inferior occipital gyrus and decreased PAS in the left dorsolateral prefrontal cortex (DLPFC), bilateral middle cingulate cortex (MCC), left inferior parietal lobule, and left cerebellum Crus I. A negative correlation was found between decreased PAS in the left DLPFC and Yale-Brown Obsessive-compulsive Scale compulsive behavior scores in the patients. Furthermore, decreased PAS in the bilateral MCC could be used to distinguish OCD from HCs with a sensitivity of 87.50%, an accuracy of 88.46%, and a specificity of 89.47%. These results highlighted the contribution of disrupted asymmetry of intra-hemispheric FC within and outside the cortico-striato-thalamocortical circuits at rest in the pathophysiology of OCD, and reduced intra-hemispheric FC in the bilateral MCC may serve as a potential biomarker to classify individuals with OCD from HCs.

Decreased Resting-State Interhemispheric Functional Connectivity in Medication-Free Obsessive-Compulsive Disorder.

OBJECTIVE: Decreased homotopic connectivity of brain networks such as the cortico-striato-thalamo-cortical (CSTC) circuits may contribute to the pathophysiology of obsessive-compulsive disorder (OCD). However, little is known about interhemispheric functional connectivity (FC) at rest in OCD. In this study, the voxel-mirrored homotopic connectivity (VMHC) method was applied to explore interhemispheric coordination at rest in OCD. METHODS: Forty medication-free patients with OCD and 38 sex-, age-, and education level-matched healthy controls (HCs) underwent a resting-state functional magnetic resonance imaging. The VMHC and support vector machine (SVM) methods were used to analyze the data. RESULTS: Patients with OCD had remarkably decreased VMHC values in the orbitofrontal cortex, thalamus, middle occipital gyrus, and precentral and postcentral gyri compared with HCs. A combination of the VMHC values in the thalamus and postcentral gyrus could optimally distinguish patients with OCD from HCs. CONCLUSIONS: Our findings highlight the contribution of decreased interhemispheric FC within and outside the CSTC circuits in OCD and provide evidence to the pathophysiology of OCD.

Altered Global Brain Functional Connectivity in Drug-Naive Patients With Obsessive-Compulsive Disorder.

Abnormal functional connectivity (FC) within discrete brain networks is involved in the pathophysiology of obsessive-compulsive disorder (OCD) with inconsistent results. In the present study, we investigated the FC patterns of 40 drug-naive patients with OCD and 38 healthy controls (HCs) through an unbiased voxel-wise global brain FC (GFC) analysis at rest. Compared with HCs, patients with OCD showed decreased GFC within the default mode network (DMN) (i.e., left posterior cingulate cortex/lingual gyrus) and sensorimotor network (i.e., left precentral gyrus/postcentral gyrus) and increased GFC within the executive control network (ECN) (i.e., left dorsal lateral prefrontal cortex and left inferior parietal lobule). Receiver operating characteristic curve analyses further indicated that the altered GFC values within the DMN, ECN, and sensorimotor network may be used as neuroimaging markers to differentiate patients with OCD from HCs. These findings indicated the aberrant FC patterns of the DMN, ECN, and sensorimotor network associated with the pathophysiology of OCD and provided new insights into the changes in brain organization function in OCD.

A pair of new enantiomers of xanthones from the stems and leaves of Cratoxylum cochinchinense.

BACKGROUND: The simple and caged xanthones from Clusiaceae showed significant antineoplastic activity. This study aims to identify structural diverse xanthones and search for novel antitumor natural products from this family plants. METHODS: The structures of new compounds 1a and 1b were elucidated mainly through comprehensive NMR and MS spectroscopic data, and their absolute configurations were determined by the comparison of the experimental and calculated electronic circular dichroism. RESULTS: A pair of new xanthone enantiomers, (+)- and (-)-cracochinxanthone A (1a and 1b), along with thirty known analogues (2-31), were isolated from extracts of the stems and leaves of C. cochinchinense. Preliminary biological assay of some isolates against HL-60, PC-3, and MDA-MB-231 cancer cell lines. CONCLUSION: Some isolated xanthones exhibited high sensitivity against three human malignant cell lines and the structure-activity relationship study showed that the prenyl and geranyl units may play an important role in antitumor activity.

New depsidone and dichromone from the stems of Garcinia paucinervis with antiproliferative activity.

A new depsidone, paucinervin Q (1), a new dichromone, paucinervin R (2), and a known compound, paucinervin B (3), were isolated from the stems of Garcinia paucinervis by various chromatographic methods. Their structures were determined by analysis of spectroscopic data. The isolates were evaluated for their antiproliferative activity against three cancer cell lines HL-60, PC-3 and CaCo-2. Compound 1 showed significant inhibitory activities.

The Effects of Ketogenic Diet Treatment in Kcna1-Null Mouse, a Model of Sudden Unexpected Death in Epilepsy.

Sudden unexpected death in epilepsy (SUDEP) is a leading cause of abrupt death in patient with epilepsy. It represents 5-30% of all rapid deaths in individuals with epilepsy. Ketogenic diet (KD) has been used in clinic for treatment of epilepsy for many decades. However, the cellular and molecular mechanisms underlying the SUDEP and the relationship between KD and SUDEP remain uncertain. Kcna1-null (Kcna1-/-) mouse, an animal model of SUDEP, is frequently used to study mechanisms underlying SUDEP. The current mini-review focus on risk factors for SUDEP and their relationship with KD treatment in Kcna1-/- mice. Emerging data suggest that factors including seizure frequency, longevity, rest, age, and gender both in Kcna1-/- mice and KD treated Kcna1-/-mice are involved in SUDEP. This provides valuable prediction for clinical application of KD for treatment of SUDEP.

Altered network homogeneity of the default-mode network in drug-naive obsessive-compulsive disorder.

BACKGROUND: Default-mode network (DMN) plays a key role in the pathophysiology of obsessive-compulsive disorder (OCD). However, the network homogeneity (NH) of DMN in OCD remains equivocal. OBJECTIVE: This study aimed to investigate abnormalities in the NH of the DMN at rest and the correlation between the NH of DMN and clinical variables in patients with OCD. METHODS: This study used the independent component analysis and unbiased hypothesis-driven NH method to analyze the resting-state functional magnetic resonance imaging data of 40 drug-naive patients with OCD and 40 age-, gender-, and education-matched healthy controls (HCs). RESULTS: Patients with OCD exhibited decreased NH values in the left ventral medial prefrontal cortex and bilateral posterior cingulate cortex (PCC)/precuneus (PCu) compared with HCs. Furthermore, analyses of receiver operating characteristic curves indicated that the decreased NH values in the right PCC/PCu may be used as a candidate neuroimaging marker to distinguish patients with OCD from HCs. CONCLUSION: These findings contribute new evidence of the participation of the altered NH of the DMN in the pathophysiology of OCD. TRIAL REGISTRATION: Study on the mechanism of brain network in obsessive-compulsive disorder with multi-model magnetic resonance imaging (ChiCTR-COC-17013301).

Chiral resolution and anticancer effect of xanthones from Garcinia paucinervis.

Bioassay-guided fractionation of the dichloromethane-soluble portion of the stems of Garcinia paucinervis led to the isolation of eight new xanthones, including three pairs of enantiomers, (+) and (-) paucinervins L-N (1a-3a, and 1b-3b), one optically pure compound, (-) paucinervin O (4), and one new analogue, paucinervin P (5), as well as thirteen known xanthones (6-18). Their structures were established by detailed analysis of extensive spectroscopic data. The absolute configurations of 1-4 were confirmed by ECD calculations. All the isolates 1-18 displayed antiproliferative effect against HL-60 with IC50 values ranging from 0.87 to 29.14 µM, of which compound 5 was the most active. Compounds 6, and 14 exhibited potential inhibitory activity against PC-3 cells, while compounds 5-7, 14, and 16-17 displayed cytotoxic potency against Caco-2 cells. A preliminary structure-activity relationship was also discussed.

A new biflavonoid and a new triterpene from the leaves of Garcinia paucinervis and their biological activities.

A new biflavonoid, paucinervin K (1) and a new triterpene, 23-hydroxy-friedelin (2), together with eleven known compounds 3-13 were isolated from the leaves of Garcinia paucinervis. Their structures, including stereochemistry, were determined by spectroscopic analysis of NMR, MS, IR and ECD calculation and the octant rule. Some of the isolated compounds were tested for antiproliferative, α-glucosidase inhibitory and antioxidant activities in vitro. Compounds 1, 3, 4, 5 and 9 showed moderate preferential antioxidant and hypoglycemic activities. Compounds 3-6 and 9 exhibited potent growth inhibition against HepG-2 and PC-3 cell lines with IC50 values ranging from 1.02-10.05 µM.