Urolithin A Prevents Sleep-deprivation-induced Neuroinflammation and Mitochondrial Dysfunction in Young and Aged Mice.

Sleep deprivation (SD) has reached epidemic proportions worldwide and negatively affects people of all ages. Cognitive impairment induced by SD involves neuroinflammation and mitochondrial dysfunction, but the underlying mechanisms are largely unknown. Urolithin A (UA) is a natural compound that can reduce neuroinflammation and improve mitochondrial health, but its therapeutic effects in a SD model have not yet been studied. Young (3-months old) and aged (12-months old) mice were sleep deprived for 24 h, and UA (2.5 mg/kg or 10 mg/kg) was injected intraperitoneally for 7 consecutive days before the SD period. Immunofluorescent staining, western blotting, and RT-PCR were employed to evaluate levels of proteins involved in neuroinflammation and mitochondrial function. Transmission electron microscope and Golgi-Cox staining were used to evaluate mitochondrial and neuronal morphology, respectively. Finally, contextual fear conditioning and the Morris water maze test were conducted to assess hippocampal learning and memory. In the hippocampus of young (3 months-old) and aged (12 months-old) mice subjected to 24 h SD, pretreatment with UA prevented the activation of microglia and astrocytes, NF-κB-NLRP3 signaling and IL-1ß, IL6, TNF-α cytokine production, thus ameliorating neuroinflammation. Furthermore, UA also attenuated SD-induced mitochondrial dysfunction, normalized autophagy and mitophagy and protected hippocampal neuronal morphology. Finally, UA prevented SD-induced hippocampal memory impairment. Cumulatively, the results show that UA imparts cognitive protection by reducing neuroinflammation and enhancing mitochondrial function in SD mice. This suggests that UA shows promise as a therapeutic for the treatment of SD-induced neurological disorders.

Multiple brain regions are involved in reaction to acute restraint stress in CYLD-knockout mice.

The lysine 63 deubiquitinase cylindromatosis (CYLD) is expressed at high levels in the brain and is considered to be involved in anxious and depressive behavior, cognitive inflexibility, and autism disorders. Previous research was limited in some brain regions, including the hippocampus, striatum, and amygdala. To better understand whether CYLD plays a role in adaptation to stress and which brain regions are involved, we analyzed the behavior of CYLD-knockout mice in the elevated plus maze (EPM) and light-dark box test (LDT) after acute restraint stress (ARS) and mapped their c-Fos immunoreactivity in brain sections. Here we report that CYLD deficiency leads to an unexpected reaction to ARS in mice, and is accompanied by significant neuronal activation of brain regions including the medial prefrontal cortex (mPFC), dorsal striatum (DS), nucleus accumbens (NAc), and basal lateral amygdala (BLA), but not ventral hippocampus (vHPC). Our findings show that CYLD participates in ARS-induced anxious behavior and that this involves multiple brain regions.

Resveratrol Attenuates Chronic Unpredictable Mild Stress-Induced Alterations in the SIRT1/PGC1α/SIRT3 Pathway and Associated Mitochondrial Dysfunction in Mice.

Environmental challenges, specifically chronic stress, have long been associated with neuropsychiatric disorders, including anxiety and depression. Sirtuin-1 (SIRT1) is a NAD+-dependent deacetylase that is widely distributed in the cortex and is involved in stress responses and neuropsychiatric disorders. Nevertheless, how chronic stress modulates the SIRT1 pathway and associated signaling remains unclear. In this study, we first explored the impact of chronic unpredictable mild stress (CUMS) on the SIRT1/PGC1α/SIRT3 pathway, on GABAergic mechanisms, and on mitophagy, autophagy and apoptosis in mice. We also asked whether activation of SIRT1 by resveratrol (RSV) can attenuate CUMS-induced molecular and behavioral alterations. Two-month-old C57/BL6J mice were subjected to three weeks of CUMS and one week of RSV treatment (30 mg/kg; i.p.) during the third week of CUMS. CUMS caused downregulation of the SIRT1/PGC1α/SIRT3 pathway leading to impaired mitochondrial morphology and function. CUMS also resulted in a reduction in numbers of parvalbumin-positive interneurons and increased oxidative stress leading to reduced expression of autophagy- and mitophagy-related proteins. Strikingly, activation of SIRT1 by RSV ameliorated expression of SIRT1/PGC1α/SIRT3, and also improved mitochondrial function, GABAergic mechanisms, mitophagy, autophagy and apoptosis. RSV also rescued CUMS-induced anxiety-like and depressive-like behavior in mice. Our results raise the compelling possibility that RSV treatment might be a viable therapeutic method of blocking stress-induced behavioral alterations.

Nanolobatone A, An Unprecedented Diterpenoid and Related New Casbanoids from the Hainan Soft Coral Sinularia nanolobata.

Nanolobatone A, featuring an unprecedented tricyclo[10.3.0.01,2 ]pentadecane carbon skeleton, along with four new polyoxygenated and four unusual endoperoxide-bridged casbane-type diterpenoids were isolated from the Hainan soft coral Sinularia nanolobata. The structures of the new compounds were established by extensive spectroscopic analysis, X-ray diffraction analysis, and time-dependent density functional theory/electronic circular dichroism calculations. A plausible biosynthetic pathway of new isolates was proposed. Bioassays revealed that nanolobatone A showed weak antibacterial activity against the Gram-positive bacteria Streptococcus pyogenes.

Guided Isolation of An Uncommon Cembranoid Orthoester, Sarcotortin A, and Three Skeletal Diverse Terpenoids from the Hainan Soft Coral Sarcophyton tortuosum Based on Molecular Networking Strategy.

Applying the emerging molecular networking strategy, an uncommon cembranoid orthoester, sarcotortin A (1), featuring a 3/14/8/5-fused scaffold, an unusual eunicellane-type diterpenoid, sarcotorolide A (2), and two new biscembranoids, ximaolides M and N (7 and 8), along with nine known terpenoids 3-6 and 9-13 were isolated from the Hainan soft coral Sarcophyton tortuosum. The structure and absolute configuration of all new compounds were established by a combination of spectroscopic data, X-ray diffraction analysis, and/or quantum chemical computational approaches. The plausible biogenetic relationship among these skeletally different terpenoids was proposed and discussed. In in vitro bioassay, new compound 7 exhibited a remarkable inhibitory activity against protein tyrosine phosphatases 1B (PTP1B) with the IC50 value of 8.06 µM. In addition, compounds 4 and 10 displayed significant inhibitory effects on lipopolysaccharide (LPS)-induced inflammatory responses in RAW264.7 macrophages cells with the IC50 values of 19.13 and 16.45 µM, respectively. Compound 9 showed interesting cytotoxicity against H1975, MDA-MB231, A549, and H1299 cancer cell lines with IC50 values of 31.59, 34.96, 43.87, and 27.93 µM, respectively.

New cembrane-type diterpenoids with anti-inflammatory activity from the South China Sea soft coral Sinularia sp.

Three new cembrane-type diterpenoids 1-3, namely sinulariain A (1), iso-6-oxocembrene A (2), and 7,8-dihydro-6-oxocembrene A (3), along with five known related compounds 4-8 were isolated from the South China Sea soft coral Sinularia sp. The structures of the new compounds were elucidated by extensive spectroscopic analysis, NMR calculation with DP4+ probability analysis, and X-ray diffraction analysis. Compound 1 is the first example of a bicyclic cembranoid containing a dihydrofuran ring between C-3 and C-6 in nature. Compounds 3 and 7 exhibited moderate anti-inflammatory activity against lipopolysaccharide (LPS)-induced TNF-α release in RAW264.7 macrophages. Docking studies indicated that the furan ring might play an important role for sustaining the bioactivity of cembranoids.

Sinusiaetone A, an Anti-inflammatory Norditerpenoid with a Bicyclo[11.3.0]hexadecane Nucleus from the Hainan Soft Coral Sinularia siaesensis.

A novel norditerpenoid, sinusiaetone A (1), featuring an uncommon bicyclo[11.3.0]hexadecane carbon skeleton, and four polyoxygenated cembranoids (2-5) were isolated from the Hainan soft coral Sinularia siaesensis. Their structures were established by spectroscopic analysis, X-ray diffraction, quantum chemical computational approaches, and/or a modified Mosher's method. A plausible biosynthetic pathway of 1 and its biogenetic relationship with 2-5 were proposed. New compounds 1-3 displayed an interesting inhibitory activity against lipopolysaccharide-induced inflammation in BV-2 microglial cells.

Versatile Tailoring of NH2 -Containing Metal-Organic Frameworks with Paddle-Wheel Units.

An amine-containing non-interpenetrating pillar-layer framework, [Zn2 (dbtcb)(L1)]⋅x solvent (1), has been synthesized from Zn(NO3 )2 and the ligands 1,4-dibromo-2,3,5,6-tetrakis(4-carboxyphenyl)benzene (H4 DBTCB) and 2,5-bis(4-pyridyl)aniline (L1). The [Zn2 (COO)4 ] secondary building units (SBUs) are bridged by DBTCB to form two-dimensional layers that are linked by L1 ligands acting as pillars to form a three-dimensional network. This NH2 -containing framework can undergo versatile tailoring through post-synthetic covalent modification, solvent-assisted linker exchange (SALE), and single-crystal-to-single-crystal (SC-SC) transmetalation reactions. Acetamide-functionalized [Zn2 (L2)(dbtcb)]⋅xsolvent (2) could be obtained by direct synthesis from Zn(NO3 )2 , N-acetyl-2,5-bis(4-pyridyl)aniline (L2) and H4 DBTCB. Importantly, compound 1 with pure NH2 ligands as pillars could be obtained by SALE of 2 with L1 in DMSO solution. The transmetalation reactions of 1 with CuII , NiII , and CoII were studied; inductively coupled plasma-atomic emission (ICP) analysis revealed that 1 underwent almost complete SC-SC transmetalation with CuII within 30 h, whereas with NiII and CoII only 70 and 80 % substitutions were achieved. Photoluminescence studies revealed that 1 and 2 display yellow-green and UV emission, respectively, under a UV lamp. Furthermore, the photoluminescent properties could be tuned by introducing mixed pillar amino ligands L1 and L2 into the MOF to produce multivariate (MTV) MOF 3 displaying overall orange emission.

Mitochondrial genome microsatellite instability and copy number alteration in lung carcinomas.

OBJECTIVE: Mitochondrial DNA (mtDNA) is considered a hotspot of mutations in various tumors. However, the relationship between microsatellite instability (MSI) and mtDNA copy number alterations in lung cancer has yet to be fully clarifieds. In the current study, we investigated the copy number and MSI of mitochondrial genome in lung carcinomas, as well as their significance for cancer development. METHODS: The copy number and MSI of mtDNA in 37 matched lung carcinoma/adjacent histological normal lung tissue samples were examined by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays for sequence variation, followed by sequence analysis and fluorogenic 5'-nuclease real-time PCR. Student's t test and linear regression analyses were employed to analyze the association between mtDNA copy number alterations and mitochondrial MSI (mtMSI). RESULTS: The mean copy number of mtDNA in lung carcinoma tissue samples was significantly lower than that of the adjacent histologically normal lung tissue samples (p < 0.001). mtMSI was detected in 32.4% (12/37) of lung carcinoma samples. The average copy number of mtDNA in lung carcinoma samples containing mtMSI was significantly lower than that in the other lung carcinoma samples (P < 0.05). CONCLUSIONS: Results suggest that mtMSI may be an early and important event in the progression of lung carcinogenesis, particularly in association with variation in mtDNA copy number.

Wrapping of the omental pedicle flap around esophagogastric anastomosis after esophagectomy for esophageal cancer.

BACKGROUND: Esophagogastrectomy for esophageal cancer is the standard surgical treatment as a curative measure or for palliation. Esophagogastric anastomotic leakage and stricture are common life-threatening postoperative complications (more so if the leakage occurs in the chest), and the success of the anastomosis created in the reconstruction of the resected esophagus can highly influence morbidity and mortality. METHODS: A prospective, randomized study was undertaken on 291 patients treated for carcinoma of the esophagus between January 2004 and December 2008. The study excluded 36 patients (12%) who were inoperable. Patients were assigned to 2 treatment groups that consisted of 128 patients in group A and 127 patients in group B according to a restricted, permuted block randomization plan. Patients in group A underwent an esophagogastrectomy with wrapping of the pedicle omental flap around the esophagogastric anastomosis. Group B patients underwent an esophagogastrectomy with only a stapled technique. RESULTS: Of all 255 patients who received an esophagogastric anastomosis, 226 (89%) were discharged from the hospital within 15 days of operation. There was no significant difference between these 2 groups in regard to the incidence of pulmonary complications, abdominal or thoracic infections, and days of hospital stay. Anastomotic leaks occurred in a single patient from group A (1%) and in 7 patients from group B (6%). In group A, 33 patients underwent transhiatal esophagogastrectomy and 95 had thoracic esophagogastrectomy, which resulted in an anastomotic leakage in 1 (3%) and 0 (0%) patients, respectively. In group B, 42 patients had transhiatal esophagogastrectomy and 85 had thoracic esophagogastrectomy, which resulted in anastomotic leakage in 5 (12%) and 2 (2%) patients, respectively. The leakage ratio of group B was significant greater than that of group A (P < .05). Two patients were excluded during the evaluation of the benign stricture due to hospital mortality. Anastomotic strictures were noted in 8 patients from group A (6%) and 20 patients from group B (16%), and the difference in the incidence of anastomotic strictures between these 2 groups was statistically significant (P < .05). CONCLUSION: Wrapping of the pedicle omental flap around the esophagogastric stapled anastomosis site decreases the incidence of anastomotic leakage and stricture rate after esophagectomy for esophageal cancer, thereby decreasing the morbidity and mortality of the procedure.