Herbal/Natural Compounds Resist Hallmarks of Brain Aging: From Molecular Mechanisms to Therapeutic Strategies.

Aging is a complex process of impaired physiological integrity and function, and is associated with increased risk of cardiovascular disease, diabetes, neurodegeneration, and cancer. The cellular environment of the aging brain exhibits perturbed bioenergetics, impaired adaptive neuroplasticity and flexibility, abnormal neuronal network activity, dysregulated neuronal Ca2+ homeostasis, accumulation of oxidatively modified molecules and organelles, and clear signs of inflammation. These changes make the aging brain susceptible to age-related diseases, such as Alzheimer's and Parkinson's diseases. In recent years, unprecedented advances have been made in the study of aging, especially the effects of herbal/natural compounds on evolutionarily conserved genetic pathways and biological processes. Here, we provide a comprehensive review of the aging process and age-related diseases, and we discuss the molecular mechanisms underlying the therapeutic properties of herbal/natural compounds against the hallmarks of brain aging.

Differences in in vivo absorption of flavone glycosides, flavone aglycones and terpene lactones under different dosage forms and physiological conditions.

ETHNOPHARMACOLOGICAL RELEVANCE: Ginkgo biloba L. extract (GBE) oral preparations have been used for many years in the prevention and treatment of cardiovascular and cerebrovascular diseases, and the main active ingredients are flavonoids and terpene lactones. Among them, the oral absorption of the prototype components of flavonoid glycosides into the blood needs to be further clarified, and the differences in the oral absorption of different components in GBE by different dosage forms and physiological conditions are not clear yet. AIM OF THE STUDY: To clarify the oral absorption of the prototype flavonoid glycosides in vivo, and to further explore the differences in the oral absorption of various active compounds under different oral dosage forms and dietary conditions. MATERIALS AND METHODS: Firstly, the target compounds were selected based on the characteristic chromatogram of GBE and literature. Then, the content differences of three different oral GBE preparations were studied, and their pharmacokinetics (PK) were compared. Finally, the PK differences of the preparations with better oral absorption under different dietary conditions were studied. RESULTS: Five flavonoid glycosides, three aglycones and four terpene lactones were selected as the research objects. The content determination results of GBE tablets, guttate pills and tinctures showed that the content of several components especially flavonoid glycosides in the tincture was higher than that of the other two preparations. After oral administration of these three preparations, the PK study showed different results from previous studies. The PK behavior of flavonoid glycosides was also determined at the same time as flavonoid glycosides and terpene lactones. and the bioavailability of flavonoid glycosides in the tincture was higher than that of the other two preparations. PK results of fasting and non-fasting showed that taking GBE tincture on an empty stomach increased the absorption of various compounds, especially flavonoid glycosides. However, due to the existence of food residues in the gastrointestinal tract, the oral bioavailability of flavonoid glycosides was significantly improved. CONCLUSIONS: This study discussed the differences in the content and oral absorption of active compounds in different oral preparations of GBE, clarified the in vivo absorption of flavonoid glycosides prototype, as well as the influence of diet on the PK of active compounds, which has certain guiding significance for the clinical application of GBE oral preparations.

Approaching the quantum limit in two-dimensional semiconductor contacts.

The development of next-generation electronics requires scaling of channel material thickness down to the two-dimensional limit while maintaining ultralow contact resistance1,2. Transition-metal dichalcogenides can sustain transistor scaling to the end of roadmap, but despite a myriad of efforts, the device performance remains contact-limited3-12. In particular, the contact resistance has not surpassed that of covalently bonded metal-semiconductor junctions owing to the intrinsic van der Waals gap, and the best contact technologies are facing stability issues3,7. Here we push the electrical contact of monolayer molybdenum disulfide close to the quantum limit by hybridization of energy bands with semi-metallic antimony ([Formula: see text]) through strong van der Waals interactions. The contacts exhibit a low contact resistance of 42 ohm micrometres and excellent stability at 125 degrees Celsius. Owing to improved contacts, short-channel molybdenum disulfide transistors show current saturation under one-volt drain bias with an on-state current of 1.23 milliamperes per micrometre, an on/off ratio over 108 and an intrinsic delay of 74 femtoseconds. These performances outperformed equivalent silicon complementary metal-oxide-semiconductor technologies and satisfied the 2028 roadmap target. We further fabricate large-area device arrays and demonstrate low variability in contact resistance, threshold voltage, subthreshold swing, on/off ratio, on-state current and transconductance13. The excellent electrical performance, stability and variability make antimony ([Formula: see text]) a promising contact technology for transition-metal-dichalcogenide-based electronics beyond silicon.

Behavior and physiology in female Cricetulus barabensis are associated with the expression of circadian genes.

The circadian clock regulates the behavior, physiology, and metabolism of mammals, and these characteristics, such as sleep-wake cycles, exercise capacity, and hormone levels, exhibit circadian rhythms. Light signaling is the main stimulator of the mammalian circadian system. The photoperiod regulates the reproductive cycle of seasonal breeding animals, and the circadian clock plays a pivotal role in this process. However, the role of the clock in coordinating animal behavior and physiology in response to photoperiodic changes needs further investigation. The present study investigated the changes and correlation of behavioral activities, physiological indicators, and gene expression in female striped hamsters (Cricetulus barabensis) within 24 h under a 12L:12D photoperiod. We found that the daily rhythms of sleep-wake and open field were significant in hamsters. The expression of clock genes, melatonin receptor genes, and genes involved in general metabolism oscillated significantly in central and peripheral tissues (brain, hypothalamus, liver, ovary, and thymus) and was significantly associated with behavior and physiology. Our results revealed that the neuroendocrine system regulated the rhythmicity of behavior and physiology, and central and peripheral clock genes (Bmal1, Clock, Per1, Per2, Cry1, and Cry2), melatonin receptor genes (MT1, MT2, and GPR50), and metabolizing genes (SIRT1, FGF21, and PPARα) played important roles. Our results suggest that central and peripheral circadian clocks, melatonin receptors, and genes involved in general metabolism may play key roles in maintaining circadian behavior and metabolic homeostasis in striped hamsters. Our results may have important implication for rodent pest control.

Precursor Quantitation Methods for Next Generation Food Production.

Food is essential for human survival. Nowadays, traditional agriculture faces challenges in balancing the need of sustainable environmental development and the rising food demand caused by an increasing population. In addition, in the emerging of consumers' awareness of health related issues bring a growing trend towards novel nature-based food additives. Synthetic biology, using engineered microbial cell factories for production of various molecules, shows great advantages for generating food alternatives and additives, which not only relieve the pressure laid on tradition agriculture, but also create a new stage in healthy and sustainable food supplement. The biosynthesis of food components (protein, fats, carbohydrates or vitamins) in engineered microbial cells often involves cellular central metabolic pathways, where common precursors are processed into different proteins and products. Quantitation of the precursors provides information of the metabolic flux and intracellular metabolic state, giving guidance for precise pathway engineering. In this review, we summarized the quantitation methods for most cellular biosynthetic precursors, including energy molecules and co-factors involved in redox-reactions. It will also be useful for studies worked on pathway engineering of other microbial-derived metabolites. Finally, advantages and limitations of each method are discussed.

MoTe2 p-n Homojunctions Defined by Ferroelectric Polarization.

Doped p-n junctions are fundamental electrical components in modern electronics and optoelectronics. Due to the development of device miniaturization, the emergence of two-dimensional (2D) materials may initiate the next technological leap toward the post-Moore era owing to their unique structures and physical properties. The purpose of fabricating 2D p-n junctions has fueled many carrier-type modulation methods, such as electrostatic doping, surface modification, and element intercalation. Here, by using the nonvolatile ferroelectric field polarized in the opposite direction, efficient carrier modulation in ambipolar molybdenum telluride (MoTe2 ) to form a p-n homojunction at the domain wall is demonstrated. The nonvolatile MoTe2 p-n junction can be converted to n-p, n-n, and p-p configurations by external gate voltage pulses. Both rectifier diodes exhibited excellent rectifying characteristics with a current on/off ratio of 5 × 105 . As a photodetector/photovoltaic, the device presents responsivity of 5 A W-1 , external quantum efficiency of 40%, specific detectivity of 3 × 1012 Jones, fast response time of 30 µs, and power conversion efficiency of 2.5% without any bias or gate voltages. The MoTe2 p-n junction presents an obvious short-wavelength infrared photoresponse at room temperature, complementing the current infrared photodetectors with the inadequacies of complementary metal-oxide-semiconductor incompatibility and cryogenic operation temperature.

Graphene Hybrid Structures for Integrated and Flexible Optoelectronics.

Graphene (Gr) has many unique properties including gapless band structure, ultrafast carrier dynamics, high carrier mobility, and flexibility, making it appealing for ultrafast, broadband, and flexible optoelectronics. To overcome its intrinsic limit of low absorption, hybrid structures are exploited to improve the device performance. Particularly, van der Waals heterostructures with different photosensitive materials and photonic structures are very effective for improving photodetection and modulation efficiency. With such hybrid structures, Gr hybrid photodetectors can operate from ultraviolet to terahertz, with significantly improved R (up to 109 A W-1 ) and bandwidth (up to 128 GHz). Furthermore, integration of Gr with silicon (Si) complementary metal-oxide-semiconductor (CMOS) circuits, the human body, and soft tissues is successfully demonstrated, opening promising opportunities for wearable sensors and biomedical electronics. Here, the recent progress in using Gr hybrid structures toward high-performance photodetectors and integrated optoelectronic applications is reviewed.

Simultaneous quantification of five biogenic amines based on LC-MS/MS and its application in honeybee venom from different subspecies.

The use of honeybee venom in traditional medicine is increasing due to its unexpected beneficial effects in the treatment of diseases. In this study, a simple and environmentally friendly sample preparation procedure was developed to quantify five biogenic amines-histamine, 5-hydroxytryptamine, dopamine, adrenaline, and noradrenaline-in honeybee venom using high-performance liquid chromatography tandem mass spectrometry. The instrument and sample preparation method were optimized to achieve stable, sensitive, and accurate quantification of the five biogenic amines. The peak purities of five biogenic amines in bee venom were examined using a diode array detector to ensure that endogenous impurities will not interfere with biogenic amines during the chromatographic separation procedure. The correlation coefficient of each compound was higher than 0.998 in the range of 0.5-1000 ng/mL. The limits of detection and quantification of the developed method ranged between 0.09 and 0.17, and 0.3 and 0.59 µg/g, respectively. The average recoveries of spiked biogenic amines with different concentrations were higher than 70.95%, and the intra- and intermediate-day precisions were lower than 7.51% and 10.17%, respectively. The carry-over between each injection and the stability of the target analytes were also evaluated to ensure the effectiveness of this method. The data obtained are presented in various formats, including boxplot, heat map, and principal component analysis diagram, to visualize the differences in the biogenic amine contents of the honeybee venoms from different subspecies. This method hopes to provide the opportunity to distinguish the bee venom produced by different subspecies.

Design, synthesis and biological evaluation of curcumin analogues as novel LSD1 inhibitors.

Histone lysine-specific demethylase 1 (LSD1) was the first discovered histone demethylase. Inactivating LSD1 or downregulating its expression inhibits cancer-cell development, and thus, it is an attractive molecular target for the development of novel cancer therapeutics. In this study, we worked on the structural optimization of natural products and identified 30 novel LSD1 inhibitors. Utilizing a structure-based drug design strategy, we designed and synthesized a series of curcumin analogues that were shown to be potent LSD1 inhibitors in the enzyme assay. Compound WB07 displayed the most potent LSD1 inhibitory activity, with an IC50 value of 0.8 µM. Moreover, WA20 showed an anticlonogenic effect on A549 cells with an IC50 value of 4.4 µM. Molecular docking simulations were also carried out, and the results indicated that the inhibitors bound to the protein active site located around the key residues of Asp555 and Asp556. These findings suggested that compounds WA20 and WB07 are the first curcumin analogue-based LSD1 inhibitors with remarkable A549 suppressive activity, providing a novel scaffold for the development of LSD1 inhibitors.

Specific cell targeting with APRPG conjugated PEG-PLGA nanoparticles for treating ovarian cancer.

Good biocompatibility, specific tumor targeting, effective drug loading capacity and persistence in the circulation in vivo are imperative prerequisites for the antitumor efficiency of nanoparticles and their further clinical application. In this study, APRPG (Ala-Pro-Arg-Pro-Gly) peptide-modified poly (ethylene glycol)-poly (lactic acid) (PEG-PLA) nanoparticles (NP-APRPG) encapsulating inhibitors of angiogenesis (TNP-470) (TNP-470-NP-APRPG) were fabricated. TNP-470-NP-APRPG was designed to feature maleimide-PEG-PLA and mPEG-PLA as carrier materials, the APRPG peptide for targeting angiogenesis, PEG for prolonging circulation in vivo and PLA for loading TNP-470. TNP-470-NP-APRPG was confirmed to be approximately 130 nm in size with negative ζ-potential (-14.3 mV), narrow distribution (PDI = 0.27) and spherical morphology according to dynamic light scattering (DLS) and transmission electron microscopy (TEM) analyses. In addition, X-ray photoelectron spectra (XPS) analyses confirmed 7.73% APRPG grafting on the TNP-470-NP. In vitro, TNP-470-NP-APRPG exhibited effective inhibition of proliferation, migration and tube formation in human umbilical vein endothelial cells (HUVECs). Similar findings were observed for the retardation of tumor growth in SKOV3 ovarian cancer-bearing mice, suggesting the significant inhibition of angiogenesis and antitumor efficiency of TNP-470-NP-APRPG. Moreover, no obvious toxic drug responses were observed. Further evidence obtained from the immunohistochemical examination demonstrated that the tumor growth inhibition was closely correlated with the high rate of apoptosis among endothelial cells and the effective blockade of endothelial cell proliferation. These results demonstrate that NP-APRPG is a promising carrier for delivering TNP-470 to treat ovarian cancer and that this approach has the potential to achieve broad tumor coverage in the clinic.