No abstract

Scope Gut dysbiosis and dysregulation of the gut‐brain‐axis contributes to the pathogenesis of hypertension. Vitamin C (VC) is a common dietary supplement that shows the ability to lower the elevated blood pressure in hypertensive animals. Thus, the hypothesis that the gut microbiota is involved in the anti‐hypertensive effect of VC is proposed. Methods and Results The changes of the gut microbiota and pathology in a spontaneously hypertensive rat (SHR) model after daily oral intake of VC in dosage of 200 or 1000 mg kg−1 are examined. After 4 weeks, the elevated blood pressure of SHRs in both VC‐treated groups is attenuated. Sequencing of the gut microbiota shows improvement in its diversity and abundance. Bioinformatic analysis suggests restored metabolism and biosynthesis‐related functions of the gut, which are confirmed by the improvement of gut pathology and integrity. Analysis of the hypothalamus paraventricular nucleus (PVN), the central pivot of blood pressure regulation, also shows reduced inflammatory responses and oxidative stress. Conclusions The reduced blood pressure, enriched gut microbiota, improved gut pathology and integrity, and reduced inflammatory responses and oxidative stress in the PVN together suggest that the anti‐hypertensive effects of VC involve reshaping of gut microbiota composition and function.

Background N-methyl-D-aspartate Receptor (NMDAR) in the hypothalamic paraventricular nucleus (PVN) plays critical roles in regulating sympathetic outflow. Studies showed that acute application of the antagonists of NMDAR or its subunits would reduce sympathetic nerve discharges. However, little is known about the effect of long-term management of NMDAR in hypertensive animals. Methods PEAQX, the specific antagonist of NMDAR subunit 2A (GluN2A) was injected into both side of the PVN of two-kidney, one clip (2K1C) renal hypertensive rats and control (normotensive rats) for three weeks. Results Three weeks of PEAQX infusion significantly reduced the blood pressure of the 2K1C rats. It managed to resume the balance between excitatory and inhibitory neural transmitters, reduce the level of pro-inflammatory cytokines and reactive oxygen species in the PVN, and reduce the level of norepinephrine in plasma of the 2K1C rats. PEAQX administration also largely reduced the transcription and translation levels of GluN2A and changed the expression levels of NMDAR subunit 1 and 2B (GluN1 and GluN2B). In addition, NMDAR was known to function through activating the extracellular regulated protein kinases (ERK) or phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathways. In our study we found that in the PVN of 2K1C rats treated with PEAQX, the phosphorylation levels of mitogen-activated protein kinase kinase (MEK), ERK1/2 and cAMP-response element binding protein (CREB) significantly reduced, while the phosphorylation level of PI3K didn’t change significantly. Conclusions Chronic blockade of GluN2A alleviates hypertension through suppression of MEK/ERK/CREB pathway.

Scolopendra subspinipes mutilans L. Koch. (SSLK) helps reduce the risk of coronary heart disease (CHD) but its effects on rheumatic heart disease (RHD) patients remain unclear. 80 RHD patients were recruited and randomly assigned into SG (to receive SSLK treatment) and CG (to receive placebo) groups, and the intervention lasted for 3 months. The following cardiac indexes were measured, including mean arterial pressure (MAP), heart rate (HR), central venous pressure (CVP), blood lactate, fatigue, shortness of breath, palpitation, and chest pain. ELISA kits were used to analyze creatine kinase isoenzyme (CK-MB), serum troponin T (cTnT), CRP, IL-1β, IL-6, and TNF-α, malondialdehyde (MDA), and superoxide dismutase (SOD). Relative percentages of CD4+CD25+FoxP3 regulatory (Treg) and CD4+IL-17 T cells were measured using flow cytometry. After 3-month therapy, SSLK intervention improved MAP, HR, CVP, fatigue, palpitation, and shortness breath of CHD patients, reduced the levels of blood lactate, CK-MB, cTnT, CRP, IL-1β, IL-6, TNF-α, MDA, and increased SOD level (p < 0.05). Meanwhile, SSLK treatment increased the percentages of CD4+CD25+FoxP3 Treg cells and reduced relative percentages of CD4+IL-17 T cells in a dose-dependent way (p < 0.05). Relative percentage of CD4+CD25+FoxP3 Treg cells had negative relationship while CD4+IL17 T cells had positive relationship with CK-MB, cTnT, CRP, and TNF-a (p < 0.01). SSLK ameliorated RHD by affecting the balance of CD4+CD25+FoxP3 Treg and CD4+IL17 T cells.

No abstract

Proteolysis Targeting Chimeras (PROTACs) represent a promising therapeutic modality to address undruggable and resistant issues in drug discovery. However, potential on‐target toxicity remains clinically challenging. We developed a generalized caging strategy to synthesize a series of stimuli‐responsive PROTACs (sr‐PROTACs) with diverse molecular blocks bearing robust and cleavable linkers, presenting “turn on” features in manipulating protein degradation. By leveraging pathological cues, such as elevated ROS, phosphatase, H2S, or hypoxia, and external triggers, such as ultraviolet light, X‐Ray, or bioorthogonal reagents, we achieved site‐specific activation and traceless release of original PROTACs through de‐caging and subsequent self‐immolative cleavage, realizing selective uptake and controlled protein degradation in vitro. Especially, in vivo study revealed that two sr‐PROTACs with phosphate‐ and fluorine‐containing cages exhibited high solubility and long plasma exposure, and were specifically activated by tumor overexpressing phosphatase or low dosage of X‐Ray irradiation in situ, leading to efficient protein degradation and potent tumor remission. With more reactive biomarkers to be screened from clinical practice, our caging library could provide a general tool to design activatable PROTACs, prodrugs, antibody drug conjugates, and smart biomaterials for personalized treatment, tissue engineering or regenerative medicine.

Proteolysis Targeting Chimeras (PROTACs) represent a promising therapeutic modality to address undruggable and resistant issues in drug discovery. However, potential on‐target toxicity remains clinically challenging. We developed a generalized caging strategy to synthesize a series of stimuli‐responsive PROTACs (sr‐PROTACs) with diverse molecular blocks bearing robust and cleavable linkers, presenting “turn on” features in manipulating protein degradation. By leveraging pathological cues, such as elevated ROS, phosphatase, H2S, or hypoxia, and external triggers, such as ultraviolet light, X‐Ray, or bioorthogonal reagents, we achieved site‐specific activation and traceless release of original PROTACs through de‐caging and subsequent self‐immolative cleavage, realizing selective uptake and controlled protein degradation in vitro. Especially, in vivo study revealed that two sr‐PROTACs with phosphate‐ and fluorine‐containing cages exhibited high solubility and long plasma exposure, and were specifically activated by tumor overexpressing phosphatase or low dosage of X‐Ray irradiation in situ, leading to efficient protein degradation and potent tumor remission. With more reactive biomarkers to be screened from clinical practice, our caging library could provide a general tool to design activatable PROTACs, prodrugs, antibody drug conjugates, and smart biomaterials for personalized treatment, tissue engineering or regenerative medicine.

Mol. Nutr. Food Res. 2021, 65, 2000885 DOI: https://doi.org/10.1002/mnfr.202000885 Hypertensive rats receiving daily oral Vitamin C intake showed reduction in their blood pressure. Analysis suggested improvements in the diversity and abundance of their gut microbiota, which contributed to restore the gut structure and function, and reduced the pro‐inflammatory cytokines in both gut and hypothalamic paraventricular nucleus. Together, Vitamin C influences the gut microbiota in achievement of its anti‐hypertensive effects. This is reported by Ying Li, Rawya Mohamed Salih Ibrahim, Hong‐Li Chi, Tong Xiao, Wen‐Jie Xia, Hong‐Bao Li, Yu‐Ming Kang in article 2000885.