Resting-State fMRI Functional Connectivity Strength Predicts Local Activity Change in the Dorsal Cingulate Cortex: A Multi-Target Focused rTMS Study.

Previous resting state functional magnetic resonance imaging (RS-fMRI) studies suggested that repetitive transcranial magnetic stimulation (rTMS) can modulate local activity in distant areas via functional connectivity (FC). A brain region has more than one connection with the superficial cortical areas. The current study proposed a multi-target focused rTMS protocol for indirectly stimulating a deep region, and to investigate 1) whether FC strength between stimulation targets (right middle frontal gyrus [rMFG] and right inferior parietal lobule [rIPL]) and effective region (dorsal anterior cingulate cortex [dACC]) can predict local activity changes of dACC and 2) whether multiple stimulation targets can focus on the dACC via FC. A total of 24 healthy participants received rTMS with two stimulation targets, both showing strong FC with the dACC. There were four rTMS conditions (>1 week apart, 10 Hz, 1800 pulses for each): rMFG-target, rIPL-target, Double-targets (900 pulses for each target), and Sham. The results failed to validate the multi-target focused rTMS hypothesis. But rMFG-target significantly decreased the local activity in the dACC. In addition, stronger dACC-rMFG FC was associated with a greater local activity change in the dACC. Future studies should use stronger FC to focus stimulation effects on the deep region.

Two new alkaloids from a strain of endophytic fungus Aspergillus sp.

19-Hydroxybrevianamide M (1) and 6 R-methoxybrevianamide V (2), two new alkaloids, were isolated from an extract of the endophytic fungus Aspergillus sp. JNU18HC0517J, together with six known analogues (3- 8). Their structures were elucidated by extensive spectroscopic analyses, NMR calculations, and ECD calculations. 6 R-methoxybrevianamide V (2) was the first L-proline indole DKP alkaloid with substitution at C-6 on the proline ring. Furthermore, the cytotoxities and antimicrobial activities of these isolated compounds were also evaluated. Compound 8 exhibited moderate antibacterial activity against Staphylococcus aureus 209 P with a minimal inhibitory concentration (MIC) value of 16 µg/ml.[Figure: see text].

Finger Tapping Task Activation vs. TMS Hotspot: Different Locations and Networks.

Both functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) have been used to non-invasively localize the human motor functional area. These locations can be clinically used as stimulation target of TMS treatment. However, it has been reported that the finger tapping fMRI activation and TMS hotspot were not well-overlapped. The aim of the current study was to measure the distance between the finger tapping fMRI activation and the TMS hotspot, and more importantly, to compare the network difference by using resting-state fMRI. Thirty healthy participants underwent resting-state fMRI, task fMRI, and then TMS hotspot localization. We found significant difference of locations between finger tapping fMRI activation and TMS hotspot. Specifically, the finger tapping fMRI activation was more lateral than the TMS hotspot in the premotor area. The fMRI activation peak and TMS hotspot were taken as seeds for resting-state functional connectivity analyses. Compared with TMS hotspot, finger tapping fMRI activation peak showed more intensive functional connectivity with, e.g., the bilateral premotor, insula, putamen, and right globus pallidus. The findings more intensive networks of finger tapping activation than TMS hotspot suggest that TMS treatment targeting on the fMRI activation area might result in more remote effects and would be more helpful for TMS treatment on movement disorders.

A comparative study of vestibular improvement and gastrointestinal effect of betahistine and gastrodin in mice.

Betahistine and gastrodin are the first-line medications for vestibular disorders in clinical practice, nevertheless, their amelioration effects on vestibular dysfunctions still lack direct comparison and their unexpected extra-vestibular effects remain elusive. Recent clinical studies have indicated that both of them may have effects on the gastrointestinal (GI) tract. Therefore, we purposed to systematically compare both vestibular and GI effects induced by betahistine and gastrodin and tried to elucidate the mechanisms underlying their GI effects. Our results showed that betahistine and gastrodin indeed had similar therapeutic effects on vestibular-associated motor dysfunction induced by unilateral labyrinthectomy. However, betahistine reduced total GI motility with gastric hypomotility and colonic hypermotility, whereas gastrodin did not influence total GI motility with only slight colonic hypermotility. In addition, betahistine, at normal dosages, induced a slight injury of gastric mucosa. These GI effects may be due to the different effects of betahistine and gastrodin on substance P and vasoactive intestinal peptide secretion in stomach and/or colon, and agonistic/anatgonistic effects of betahistine on histamine H1 and H3 receptors expressed in GI mucosal cells and H3 receptors distributed on nerves within the myenteric and submucosal plexuses. Furthermore, treatment of betahistine and gastrodin had potential effects on gut microbiota composition, which could lead to changes in host-microbiota homeostasis in turn. These results demonstrate that gastrodin has a consistent improvement effect on vestibular functions compared with betahistine but less effect on GI functions and gut microbiota, suggesting that gastrodin may be more suitable for vestibular disease patients with GI dysfunction.

16-Isopropyl-5,9-dimethyl-tetra-cyclo-[10.2.2.0.0]hexa-dec-15-ene-5,13,14-tricarboxylic acid dimethyl-formamide disolvate.

The title compound, C(24)H(34)O(6)·2C(3)H(7)NO, which was isolated from fumaric-modified rosin, has four asymmetrically fused six-membered rings and three carboxylic acid substituents. It contains two fused and unbridged cyclo-hexane rings, which form a trans ring junction with a chair conformation. The asymmetric unit includes one fumaropimaric acid and two dimethyl-formamide mol-ecules. The crystal structure is stabilized through inter-molecular O-H⋯O hydrogen bonds between dimethyl-formamide and fumaropimaric acid.

High-Frequency rTMS of the Motor Cortex Modulates Cerebellar and Widespread Activity as Revealed by SVM.

Functional magnetic resonance imaging (fMRI) studies have shown that the effect of repetitive transcranial magnetic stimulation (rTMS) can induce changes in remote brain regions. In the stimulated regions, low-frequency (≤1 Hz) rTMS induces inhibitory effects, while high-frequency (≥5 Hz) stimulation induces excitatory effects. However, these stereotypical effects arising from low- and high-frequency stimulation are based on measurements of motor evoked potentials (MEPs) induced by pulsed stimulation. To test the effects of rTMS on remote brain regions, the current study recruited 31 young healthy adults who participated in three rTMS sessions (10 Hz high frequency, 1 Hz low frequency, and sham) on three separate days. The stimulation target was based on individual fMRI activation in the motor cortex evoked by a finger movement task. Pre- and post-rTMS resting-state fMRI (RS-fMRI) were acquired. Regional homogeneity (ReHo) and degree centrality (DC) were calculated to measure the local and global connectivity, respectively. Compared with the sham session, high-frequency (10 Hz) rTMS significantly increased ReHo and DC in the right cerebellum, while low-frequency (1 Hz) stimulation did not significantly alter ReHo or DC. Then, using a newly developed PAIR support vector machine (SVM) method, we achieved accuracy of 93.18-97.24% by split-half validation for pairwise comparisons between conditions for ReHo or DC. While the univariate analyses suggest that high-frequency rTMS of the left motor cortex could affect distant brain activity in the right cerebellum, the multivariate SVM results suggest that both high- and low-frequency rTMS significantly modulated widespread brain activity. The current findings are useful for increasing the understanding of the mechanisms of rTMS, as well as guiding precise individualized rTMS treatment of movement disorders.

15-Hydroxy-ethyl-19-isopropyl-5,9-dimethyl-14,16-dioxo-15-aza-penta-cyclo-[10.5.2.0.0.0]nona-dec-18-ene-5-carboxylic acid.

The title compound, C(26)H(37)NO(5), which was synthesized from monoethano-lamine and maleopimaric acid, consists of two fused and unbridged cyclo-hexane rings. They form a trans ring junction with a chair conformation. The two methyl groups are in axial positions. In the crystal, inter-molecular O-H⋯O hydrogen bonds link adjacent mol-ecules into a layer structure. Two C-H⋯O interactions are also present.

2-Hydr-oxy-6,6-dimethyl-bicyclo-[3.1.1]heptane-2-carboxylic acid.

The title compound, C(10)H(16)O(3), with a bicyclo-[3.1.1]heptane unit, was obtained by oxidation of ß-pinene. The asymmetric unit contains two independent mol-ecules with similar geometry: the six-membered rings in both mol-ecules adopt envelope conformations. In the crystal, the independent mol-ecules exist as O-H⋯O hydrogen-bonded dimers. The dimers are linked into helical chains along the b axis by O-H⋯O hydrogen bonds.

16-Isopropyl-5,9-dimethyltetra-cyclo-[10.2.2.0.0]hexa-dec-15-ene-5,14-dicarboxylic acid ethanol hemisolvate.

In the title compound, C(23)H(34)O(4)·0.5C(2)H(6)O, which was isolated from acrylic modified rosin, the endocyclic compound adopts a tetra-cyclo-[10.2.2.01,10.04,9]hexa-decane structure. In the crystal, the components are linked by O-H⋯O and C-H⋯ hydrogen bonds.

Curcumin cytotoxicity is enhanced by PTEN disruption in colorectal cancer cells.

AIM: To investigate the effects of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) deficiency on the cytotoxicity of chemotherapeutic agents toward colorectal cancer cells. METHODS: PTEN-deficient colorectal cancer (CRC) cells were generated by human somatic cell gene targeting using the adeno-associated virus system. The cytotoxic effects of compounds including curcumin, 5-fluorouracil (5-FU), dihydroartemisinin (DHA), irinotecan (CPT-11) and oxaliplatin (OXA) on cancer cells were determined using the MTT assay. Enhanced cytotoxicity of curcumin in PTEN-deficient CRC cells was observed, and this was confirmed using clonogenic assays. Apoptosis and cell cycle progression were analyzed by flow cytometry. Levels of apoptosis and cell cycle-related proteins were examined by Western blotting. RESULTS: We developed an isogenic set of CRC cell lines that differed only in their PTEN status. Using this set of cell lines, we found that disruption of the PTEN gene had no effect on the sensitivity of CRC cells to 5-FU, CPT-11, DHA, or OXA, whereas PTEN disruption increased the sensitivity of CRC cells to curcumin. Loss of PTEN did not alter the curcumin-induced apoptosis in CRC cells. However, PTEN deficiency led to an altered pattern of curcumin-mediated cell cycle arrest. In HCT116 PTEN (+/+) cells, curcumin caused a G2/M phase arrest, whereas it caused a G0/G1 phase arrest in HCT116 PTEN (-/-) cells. Levels of cell cycle-related proteins were consistent with these respective patterns of cell cycle arrest. CONCLUSION: Curcumin shows enhanced cytotoxicity toward PTEN-deficient cancer cells, suggesting that it might be a potential chemotherapeutic agent for cancers harboring PTEN mutations.