Dexmedetomidine attenuates acute stress-impaired learning and memory in mice by maintaining the homeostasis of intestinal flora.

Dexmedetomidine (Dex) has been used in surgery to improve patients' postoperative cognitive function. However, the role of Dex in stress-induced anxiety-like behaviors and cognitive impairment is still unclear. In this study, we tested the role of Dex in anxiety-like behavior and cognitive impairment induced by acute restrictive stress and analyzed the alterations of the intestinal flora to explore the possible mechanism. Behavioral and cognitive tests, including open field test, elevated plus-maze test, novel object recognition test, and Barnes maze test, were performed. Intestinal gut Microbe 16S rRNA sequencing was analyzed. We found that intraperitoneal injection of Dex significantly improved acute restrictive stress-induced anxiety-like behavior, recognition, and memory impairment. After habituation in the environment, mice (male, 8 weeks, 18-23 g) were randomly divided into a control group (control, N = 10), dexmedetomidine group (Dex, N = 10), AS with normal saline group (AS + NS, N = 10) and AS with dexmedetomidine group (AS + Dex, N = 10). By the analysis of intestinal flora, we found that acute stress caused intestinal flora disorder in mice. Dex intervention changed the composition of the intestinal flora of acute stress mice, stabilized the ecology of the intestinal flora, and significantly increased the levels of Blautia (A genus of anaerobic bacteria) and Coprobacillus. These findings suggest that Dex attenuates acute stress-impaired learning and memory in mice by maintaining the homeostasis of intestinal flora.

Androgen signaling stabilizes genomes to counteract senescence by promoting XRCC4 transcription.

Aging is accompanied by a decreased DNA repair capacity, which might contribute to age-associated functional decline in multiple tissues. Disruption in hormone signaling, associated with reproductive organ dysfunction, is an early event of age-related tissue degeneration, but whether it impacts DNA repair in nonreproductive organs remains elusive. Using skin fibroblasts derived from healthy donors with a broad age range, we show here that the downregulation of expression of XRCC4, a factor involved in nonhomologous end-joining (NHEJ) repair, which is the dominant pathway to repair somatic double-strand breaks, is mediated through transcriptional mechanisms. We show that the androgen receptor (AR), whose expression is also reduced during aging, directly binds to and enhances the activity of the XRCC4 promoter, facilitating XRCC4 transcription and thus stabilizing the genome. We also demonstrate that dihydrotestosterone (DHT), a powerful AR agonist, restores XRCC4 expression and stabilizes the genome in different models of cellular aging. Moreover, DHT treatment reverses senescence-associated phenotypes, opening a potential avenue to aging interventions in the future.

Machine learning prediction of neurocognitive impairment among people with HIV using clinical and multimodal magnetic resonance imaging data.

Diagnosis of HIV-associated neurocognitive impairment (NCI) continues to be a clinical challenge. The purpose of this study was to develop a prediction model for NCI among people with HIV using clinical- and magnetic resonance imaging (MRI)-derived features. The sample included 101 adults with chronic HIV disease. NCI was determined using a standardized neuropsychological testing battery comprised of seven domains. MRI features included gray matter volume from high-resolution anatomical scans and white matter integrity from diffusion-weighted imaging. Clinical features included demographics, substance use, and routine laboratory tests. Least Absolute Shrinkage and Selection Operator Logistic regression was used to perform variable selection on MRI features. These features were subsequently used to train a support vector machine (SVM) to predict NCI. Three different classification tasks were performed: one used only clinical features; a second used only selected MRI features; a third used both clinical and selected MRI features. Model performance was evaluated by area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity with a tenfold cross-validation. The SVM classifier that combined selected MRI with clinical features outperformed the model using clinical features or MRI features alone (AUC: 0.83 vs. 0.62 vs. 0.79; accuracy: 0.80 vs. 0.65 vs. 0.72; sensitivity: 0.86 vs. 0.85 vs. 0.86; specificity: 0.71 vs. 0.37 vs. 0.52). Our results provide preliminary evidence that combining clinical and MRI features can increase accuracy in predicting NCI and could be developed as a potential tool for NCI diagnosis in HIV clinical practice.

Antistress and anti-aging activities of Caenorhabditis elegans were enhanced by Momordica saponin extract.

BACKGROUND: Momordica saponin extract (MSE) was found to not only improve longevity and neuroprotection but also alleviate fat accumulation in Caenorhabditis elegans in our previous study. However, the lipid-lowering activity of MSE alone could not fully explain its ability to improve health, so the antistress effects of MSE were further studied. METHODS: Using C. elegans as an in vivo animal, the lifespan of MSE-treated C. elegans under various stressors (H2O2, paraquat and heat) and normal conditions was studied. Furthermore, the antioxidant activities of MSE were discussed. To study the underlying mechanisms, the expression of stress resistance genes and the resistance of related mutants to H2O2 stress were tested. RESULTS: MSE significantly improved the lifespan of C. elegans under stress and normal conditions. Meanwhile, the mobility of C. elegans was also improved. Moreover, the activities of SOD and CAT and the ratio of GSH/GSSG were elevated. Consistently, the levels of ROS and lipid oxidation (the NEFA and MDA content) were reduced. Furthermore, MSE treatment upregulated the expression of the sod-3, sod-5, clt-1, clt-2, hsp-16.1 and hsp-16.2 genes. All biomarkers indicated that the antistress and anti-aging activities of MSE were due to its strong antioxidant activities. Finally, MSE induced nuclear DAF-16::GFP localization. Studies with mutants revealed that skn-1 and hsf-1 were involved in the activity of MSE, which might upregulate the expression of downstream stress-responsive genes. CONCLUSIONS: Therefore, in addition to its lipid-lowering property, the ability of MSE to improve healthspan was also attributed to the stress resistance effect. Together, MSE might serve as a lead nutraceutical in geriatric research.

Effect of Momordica saponin- and Cyclocarya paliurus polysaccharide-enriched beverages on oxidative stress and fat accumulation in Caenorhabditis elegans.

BACKGROUND: As an edible and medicinal herb in Chinese folk medicine, Cyclocarya paliurus (Batal.) Iljinskaja leaves are traditionally widely used in the treatment of metabolic disorders. The vegetable Momordica charantia L. has been consumed worldwide for thousands of years as a traditional drug due to its activities against obesity and diabetes. In view of the therapeutic value of Momordica saponins (MSs) and C. paliurus polysaccharides (CPPs), an independently developed MSs- and CPPs-containing beverage (MC) was evaluated for its efficacy in controlling oxidative stress and obesity in Caenorhabditis elegans. RESULTS: First, we found that MC could promote the nuclear localization of DAF-16 and the translation of SOD-3. Further exploring its antioxidant properties, the oxidative stress by-products reactive oxygen species, malondialdehyde, and nonesterified fatty acids were significantly inhibited in C. elegans. Moreover, damage due to diseases related to oxidative stress (age pigments and neurodegenerative diseases) was alleviated. Furthermore, fat accumulation was significantly reduced in normal and high-fat models. Finally, the lipid-lowering effects of MC might involve reductions in the size and number of lipid droplets without impairing basic physiological functions in C. elegans. CONCLUSION: These results provide promising data indicating MC as an innovative health beverage for the pharmacological management of oxidative stress and obesity. © 2020 Society of Chemical Industry.

Anti-fat effect and mechanism of polysaccharide-enriched extract from Cyclocarya paliurus (Batal.) Iljinskaja in Caenorhabditis elegans.

Obesity is a global epidemic. Recent studies have shown that Cyclocarya paliurus (C. paliurus) leaves have the potential to alleviate fat deposits. However, the fat-reducing mechanism of it remains unclear. Using Caenorhabditis elegans (C. elegans) as a model, we found that C. paliurus polysaccharide (CPP) significantly decreased fat storage in both normal and high-fat worms without affecting the movement. Moreover, the size and number of lipid droplets were reduced in CPP-treated ZXW618 worms. In energy metabolism, CPP decreased Escherichia coli (E. coli) OP50 growth and pharyngeal pumping and increased the expression of vit-2. In lipid metabolism, CPP down-regulated the expression of the sbp-1 and nhr-49 genes by modulating mdt-15 to prevent the expression of the Δ9-desaturase genes (fat-5, fat-6 and fat-7). Meanwhile, the expression of the acs-2 genes, the downstream of nhr-49, was suppressed by CPP. These findings provided insights into the CPP-induced anti-fat mechanisms, which contributed to the application of CPP in anti-obesity drugs.

Combination of PET and CXCR4-Targeted Peptide Molecule Agents for Noninvasive Tumor Monitoring.

Precision medicine is emphasizing not only at individual but also at disease molecule level in modern medicine. Therefore, target-specific molecular agents are crucial for precise diagnosis and treatment. We developed a peptide agent that binds a critical chemokine receptor-CXCR4 and could be used to detect tumor status. Confocal images showed binding of the peptide agent to human osteosarcoma cells. Clinical gold-standard molecular imaging agent PET showed tumors had high glucose metabolism, CT showed that these xenograft tumors were calcified and displayed hypervascularity. Peptide imaging demonstrated that these tumors were CXCR4 positive. However, Western blot protein analysis revealed a discordance between the tumor and the CXCR4 targeted agent, suggesting that small changes in peptide sequences have profound effect on binding to their targets. We also demonstrated the molecular screening by modifying the peptide sequence and thereby altering the binding properties of the agent. In conclusion, this study demonstrates that small molecule peptide agents can be used as an additional diagnostic tool for precision medicine.

Effects of Momordica saponin extract on alleviating fat accumulation in Caenorhabditis elegans.

Momordica saponins have diverse biological activities and are widely used to improve obesity. Here, we investigated the alleviation of fat accumulation and mechanism of action of the saponin-enriched ethanol extract from Momordica charantia (MSE) in Caenorhabditis elegans (C. elegans). First, MSE had a strong fat-reduction capacity in normal and high-fat worms. Second, MSE significantly increased the proportion of small lipid droplets and reduced the average particle size in ZXW618. Meanwhile, it improved lifespan and healthspan and physiological functions, such as age pigmentation and neuroprotection. Furthermore, MSE mediated fat reduction gets involved neither in energy intake nor in energy expenditure. Finally, MSE might down-regulate sbp-1 and nhr-49 via mdt-15, and up regulate age-1 via daf-2. And these targets genes together down-regulated the expression of fat-5, fat-6 and fat-7 to decrease fat accumulation. Our results provided new insights into the inhibition of fat accumulation and underlying mechanisms of Momordica saponins in C. elegans, which might be developed into a nutraceutical to ameliorate obesity.

Microbial community and treatment ability investigation in AOAO process for the optoelectronic wastewater treatment using PCR-DGGE biotechnology.

This study aimed to explore the microbial community variation and treatment ability of a full-scale anoxic-aerobic-anoxic-aerobic (AOAO) process used for optoelectronic wastewater treatment. The sludge samples in the biological treatment units were collected and subsequently subjected to polymerase chain reaction (PCR) amplification and denaturing gradient gel electrophoresis identification and the wastewater components such as BOD5 and NH3-N were evaluated during the processes. The group specific primers selected were targeting at the kingdom Bacteria, the Acidobacterium, the α-proteobacteria, the ß-proteobacteria ammonia oxidizers, Actinobacteria and methyllotrophs, and the 16S rDNA clone libraries were established. Ten different clones were obtained using the Bacteria primers and eight different clones were obtained using the ß-proteobacteria ammonia oxidizer primers. Over 95 % of BOD5 and 90 % of NH3-N were removed from the system. The microbial community analysis showed that the Janthinobacterium sp. An8 and Nitrosospira sp. were the dominant species throughout the AOAO process. Across the whole clone library, six clones showed closely related to Janthinobacterium sp. and these species seemed to be the dominant species with more than 50 % occupancy of the total population. Nitrosospira sp. was the predominant species within the ß-proteobacteria and occupied more than 30 % of the total population in the system. These two strains were the novel species specific to the AOAO process for optoelectronic treatment, and they were found strongly related to the system capability of removing aquatic contaminants by inspecting the wastewater concentration variation across the system.