Circadian clock genes serve as the molecular basis for animals’ ~24-h internal timekeeping. Clock gene expression inside and outside of the mammalian brain’s circadian pacemaker (i.e. the SCN) integrates temporal information into a wealth of physiological processes. Ample data suggests that in addition to canonical cellular timekeeping functions, clock proteins also interact with proteins involved in cellular processes not related to timekeeping, including protein regulation and the interaction with other signaling mechanisms not directly linked to the regulation of circadian rhythms. Indeed, recent data suggests that clock genes outside the SCN are involved in fundamental brain processes such as sleep/wakefulness, stress and memory. The role of clock genes in these brain processes are complex and divers, influencing many molecular pathways and phenotypes. In this review, we will discuss recent work on the involvement of clock genes in sleep, stress, and memory. Moreover, we raise the controversial possibility that these functions may be under certain circumstances independent of their circadian timekeeping function.

Hypertension in obesity has become a major threat for public health. Omentin-1, a novel adipokine, is down-regulated in obesity. Tetrahydroxystilbene glycoside (TSG) is the main ingredient extracted from Polygonum multiflorum Thunb (PMT), a traditional Chinese medicinal herb safely used for protecting cardiovascular systems over bimillennium. This study aims to examine (i) the impact of omentin-1 downregulation on obesity-related hypertension in murine models and the underlying mechanisms; (ii) whether tetrahydroxystilbene glycoside (TSG) improved endothelial dysfunction and obesity-associated hypertension via the increase of omentin-1.

(TSG-treated) male Zucker diabetic fatty (ZDF) rats and omentin-1 knockout (OMT

) mice were used. In vitro, human umbilical vein endothelial cells (HUVECs) and mature adipocytes differentiated from human visceral preadipocyte (HPA-v) were maintained in a co-culture system.

TSG was the main active component of PMT reducing systolic blood pressure and improving endotheliag and attenuating oxidative/nitrative stress. These results suggest that TSG could be developed as a promising anti-hypertension agent that protects against endothelial dysfunction and obesity-associated cardiovascular diseases.

Down-regulation of omentin-1 induces endothelial dysfunction and hypertension in obesity. TSG treatment (at least partially) increases omentin-1 via promoting binding of PPAR-γ and Itln-1 promoter in adipose tissues, subsequently exerts protective effects on endothelial function via activating Akt/eNOS/NO signaling and attenuating oxidative/nitrative stress. These results suggest that TSG could be developed as a promising anti-hypertension agent that protects against endothelial dysfunction and obesity-associated cardiovascular diseases.Melanopsin retinal ganglion cells (mRGCs) are intrinsically photosensitive photoreceptors contributing both to image and non-image-forming (NIF) functions of the eye. They convey light signal to the brain to modulate circadian entrainment, sleep, alertness, cognition, brightness perception and coarse vision. Given that rods and cones also contribute to all these impacts of light, isolating mRGC visual and NIF roles in humans is challenging so that mRGC functions remains to be fully characterized. Here, we evaluated light-driven visual and cognitive brain responses in Leber’s Hereditary Optic Neuropathy (LHON), an inherited optic neuropathy that is characterized by a selective relative sparing of the melanopsin-expressing retinal ganglion cells (mRGCs). Twelve patients and twelve matched healthy controls (HC) were enrolled in a functional brain magnetic resonance imaging (fMRI) protocol including visual and visual-cognitive paradigms under blue (480 nm) and red (620 nm) light exposures. Primary visual cortex activation was detected in LHON patients; in particular higher occipital activation was found in response to sustained blue vs. red stimulation in LHON vs. HC. Similarly, brain responses to the executive task were larger under blue vs. red light in LHON over lateral prefrontal cortex. These findings are in line with the relative mRGC sparing demonstrated in LHON and support the mRGC contribution to both non-visual and visual brain functions, with potential implication for visual rehabilitation in hereditary optic neuropathy patients.CRISPR-based therapeutics have entered clinical trials but no methods to inhibit Cas enzymes have been demonstrated in a clinical setting. The ability to inhibit CRISPR-based gene editing or gene targeting drugs should be considered a critical step in establishing safety standards for many CRISPR-Cas therapeutics. Inhibitors can act as a failsafe or as an adjuvant to reduce off-target effects in patients. In this review we discuss the need for clinical inhibition of CRISPR-Cas systems and three existing inhibitor technologies anti-CRISPR (Acr) proteins, small molecule Cas inhibitors, and small nucleic acid-based CRISPR inhibitors, CRISPR SNuBs. Due to their unique properties and the recent successes of other nucleic acid-based therapeutics, CRISPR SNuBs appear poised for clinical application in the near-term.Canthin-6-one (Cant) is an indole alkaloid found in several botanical drugs used as medicines, reported to be gastroprotective, anti-inflammatory, anti-microbial, anti-diarrheal and anti-proliferative. We aimed to explore Cant in the management of colitis using a trinitrobenzenesulfonic acid (TNBS)-induced rat model. A2ti-2 mouse Cant (1, 5 and 25 mg/kg) was administered by oral gavage to Wistar rats followed by induction of colitis with TNBS. Macroscopic and histopathological scores, myeloperoxidase (MPO), malondialdehyde (MDA) and reduced glutathione (GSH) were assessed in colon tissues. Pro- (TNF-α, IL-1β and IL-12p70) and anti-inflammatory (IL-10) cytokines, and vascular endothelial growth factor (VEGF) were also quantified. Mitogen-activated protein kinase 14 (MAPK14) and Toll-like receptor-8 (TLR8), as putative targets, were considered through in silico analysis. Cant (5 and 25 mg/kg) reduced macroscopic and histological colon damage scores in TNBS-treated rats. MPO and MDA were reduced by up to 61.69% and 92.45%, respectively, compared to TNBS-treated rats alone.