Exercise interventions for the effect of endothelial function in hypertensive patients: A systematic review and meta-analysis.

Endothelial dysfunction is crucial factor to the hypertension occurrence, and controversy remains regarding the effect of exercise on improving endothelial function in hypertensive patients. The authors used meta-analysis to evaluate the intervention effect of exercise on endothelial function in hypertensive patients and to investigate exercise protocols that may have a greater intervention effect. A total of 37 studies and a total of 2801 participants were included. The results were as follows: endogenous nitric oxide (NO)[SMD = .89, 95% CI (.48, 1.30), p < .0001], endothelin-1 (ET-1): [SMD = -.94, 95% CI (-1.15, -.73), p <. 0001], flow-mediated dilation (FMD) [SMD = -.57, 95% CI (.36, .79), p < .000001]. In subgroup analysis, high-intensity aerobic exercise, with a single exercise duration of 35-50 min, 3-4 times/week for a total of 10-12 weeks, had the largest amount of intervention effect on NO, and moderate-intensity resistance exercise, with a single exercise duration of ≥60 min, 6 times/week for a total of 15-18 weeks, had the largest amount of intervention effect on ET-1. In conclusion, exercise can improve NO levels, FDM levels, and reduce ET-1 secretion of hypertension patients, thereby improve their endothelial function. The ideal intervention effect of improving NO level was more likely to be obtained by taking the exercise prescription of high-intensity aerobic exercise with a single exercise duration of 35-50 min, 3-4 times/week for 10-12 weeks; the ideal intervention effect of improving ET-1 was more likely to be obtained by taking the exercise prescription of oderate -intensity resistance exercise with a single exercise duration of ≥60 min, 6 times/week for 15-18 weeks.

In situ Light-Writable Orientation Control in Liquid Crystal Elastomer Film Enabled by Chalcones.

Liquid crystal elastomers (LCEs) are stimulus-responsive materials with intrinsic anisotropy. However, it is still challenging to in situ program the mesogen alignment to realize three-dimensional (3D) deformations with high-resolution patterned structures. This work presents a feasible strategy to program the anisotropy of LCEs by using chalcone mesogens that can undergo a photoinduced cycloaddition reaction under linear polarized light. It is shown that by controlling the polarization director and the irradiation region, patterned alignment distribution in a freestanding LCE film can be created, which leads to complex and reversible 3D shape-morphing behaviors. The work demonstrates an in situ light-writing method to achieve sophisticated topography changes in LCEs, which has potential applications in encryption, sensors, and beyond.

Circularly Polarized Organic Ultralong Room-Temperature Phosphorescence with A High Dissymmetry Factor in Chiral Helical Superstructures.

Long-lived room-temperature phosphorescence (RTP) of organic materials holds a significant potential for optical information. Circularly polarized organic ultralong room-temperature phosphorescence (CP-OURTP) with extremely high dissymmetry factor (glum ) values is even highly demanded and considerably challenging. Here, an effective strategy is introduced to realize CP-OURTP with an emission decay time of 735 ms and a glum value up to 1.49, which exceeds two orders of magnitude larger than previous records, through a system composed of RTP polymers and chiral helical superstructures. The system exhibits excellent stability under multiple cycles of photoirradiation and thermal treatment, and is further employed for information encryption based on optical multiplexing. The results are anticipated to lay the foundation for the development of CP-OURTP materials in advanced photonic applications.

Increased Ca2+ Transient Underlies RyR2-Related Left Ventricular Noncompaction.

BACKGROUND: A loss-of-function cardiac ryanodine receptor (RyR2) mutation, I4855M+/-, has recently been linked to a new cardiac disorder termed RyR2 Ca2+ release deficiency syndrome (CRDS) as well as left ventricular noncompaction (LVNC). The mechanism by which RyR2 loss-of-function causes CRDS has been extensively studied, but the mechanism underlying RyR2 loss-of-function-associated LVNC is unknown. Here, we determined the impact of a CRDS-LVNC-associated RyR2-I4855M+/- loss-of-function mutation on cardiac structure and function. METHODS: We generated a mouse model expressing the CRDS-LVNC-associated RyR2-I4855M+/- mutation. Histological analysis, echocardiography, ECG recording, and intact heart Ca2+ imaging were performed to characterize the structural and functional consequences of the RyR2-I4855M+/- mutation. RESULTS: As in humans, RyR2-I4855M+/- mice displayed LVNC characterized by cardiac hypertrabeculation and noncompaction. RyR2-I4855M+/- mice were highly susceptible to electrical stimulation-induced ventricular arrhythmias but protected from stress-induced ventricular arrhythmias. Unexpectedly, the RyR2-I4855M+/- mutation increased the peak Ca2+ transient but did not alter the L-type Ca2+ current, suggesting an increase in Ca2+-induced Ca2+ release gain. The RyR2-I4855M+/- mutation abolished sarcoplasmic reticulum store overload-induced Ca2+ release or Ca2+ leak, elevated sarcoplasmic reticulum Ca2+ load, prolonged Ca2+ transient decay, and elevated end-diastolic Ca2+ level upon rapid pacing. Immunoblotting revealed increased level of phosphorylated CaMKII (Ca2+-calmodulin dependent protein kinases II) but unchanged levels of CaMKII, calcineurin, and other Ca2+ handling proteins in the RyR2-I4855M+/- mutant compared with wild type. CONCLUSIONS: The RyR2-I4855M+/- mutant mice represent the first RyR2-associated LVNC animal model that recapitulates the CRDS-LVNC overlapping phenotype in humans. The RyR2-I4855M+/- mutation increases the peak Ca2+ transient by increasing the Ca2+-induced Ca2+ release gain and the end-diastolic Ca2+ level by prolonging Ca2+ transient decay. Our data suggest that the increased peak-systolic and end-diastolic Ca2+ levels may underlie RyR2-associated LVNC.

Subcellular localization of hippocampal ryanodine receptor 2 and its role in neuronal excitability and memory.

Ryanodine receptor 2 (RyR2) is abundantly expressed in the heart and brain. Mutations in RyR2 are associated with both cardiac arrhythmias and intellectual disability. While the mechanisms of RyR2-linked arrhythmias are well characterized, little is known about the mechanism underlying RyR2-associated intellectual disability. Here, we employed a mouse model expressing a green fluorescent protein (GFP)-tagged RyR2 and a specific GFP probe to determine the subcellular localization of RyR2 in hippocampus. GFP-RyR2 was predominantly detected in the soma and dendrites, but not the dendritic spines of CA1 pyramidal neurons or dentate gyrus granular neurons. GFP-RyR2 was also detected within the mossy fibers in the stratum lucidum of CA3, but not in the presynaptic terminals of CA1 neurons. An arrhythmogenic RyR2-R4496C+/- mutation downregulated the A-type K+ current and increased membrane excitability, but had little effect on the afterhyperpolarization current or presynaptic facilitation of CA1 neurons. The RyR2-R4496C+/- mutation also impaired hippocampal long-term potentiation, learning, and memory. These data reveal the precise subcellular distribution of hippocampal RyR2 and its important role in neuronal excitability, learning, and memory.

Limiting RyR2 open time prevents Alzheimer's disease-related deficits in the 3xTG-AD mouse model.

Increasing evidence suggests that Alzheimer's disease (AD) progression is driven by a vicious cycle of soluble ß-amyloid (Aß)-induced neuronal hyperactivity. Thus, breaking this vicious cycle by suppressing neuronal hyperactivity may represent a logical approach to stopping AD progression. In support of this, we have recently shown that genetically and pharmacologically limiting ryanodine receptor 2 (RyR2) open time prevented neuronal hyperactivity, memory impairment, dendritic spine loss, and neuronal cell death in a rapid, early onset AD mouse model (5xFAD). Here, we assessed the impact of limiting RyR2 open time on AD-related deficits in a relatively late occurring, slow developing AD mouse model (3xTG-AD) that bears more resemblance (compared to 5xFAD) to that of human AD. Using behavioral tests, long-term potentiation recordings, and Golgi and Nissl staining, we found that the RyR2-E4872Q mutation, which markedly shortens the open duration of the RyR2 channel, prevented learning and memory impairment, defective long-term potentiation, dendritic spine loss, and neuronal cell death in the 3xTG-AD mice. Furthermore, pharmacologically shortening the RyR2 open time with R-carvedilol rescued these AD-related deficits in 3xTG mice. Therefore, limiting RyR2 open time may offer a promising, neuronal hyperactivity-targeted anti-AD strategy.

Limiting RyR2 Open Time Prevents Alzheimer's Disease-Related Neuronal Hyperactivity and Memory Loss but Not ß-Amyloid Accumulation.

Neuronal hyperactivity is an early primary dysfunction in Alzheimer's disease (AD) in humans and animal models, but effective neuronal hyperactivity-directed anti-AD therapeutic agents are lacking. Here we define a previously unknown mode of ryanodine receptor 2 (RyR2) control of neuronal hyperactivity and AD progression. We show that a single RyR2 point mutation, E4872Q, which reduces RyR2 open time, prevents hyperexcitability, hyperactivity, memory impairment, neuronal cell death, and dendritic spine loss in a severe early-onset AD mouse model (5xFAD). The RyR2-E4872Q mutation upregulates hippocampal CA1-pyramidal cell A-type K+ current, a well-known neuronal excitability control that is downregulated in AD. Pharmacologically limiting RyR2 open time with the R-carvedilol enantiomer (but not racemic carvedilol) prevents and rescues neuronal hyperactivity, memory impairment, and neuron loss even in late stages of AD. These AD-related deficits are prevented even with continued ß-amyloid accumulation. Thus, limiting RyR2 open time may be a hyperactivity-directed, non-ß-amyloid-targeted anti-AD strategy.

Selective activation of TWIK-related acid-sensitive K+ 3 subunit-containing channels is analgesic in rodent models.

The paucity of selective agonists for TWIK-related acid-sensitive K+ 3 (TASK-3) channel, a member of two-pore domain K+ (K2P) channels, has contributed to our limited understanding of its biological functions. By targeting a druggable transmembrane cavity using a structure-based drug design approach, we discovered a biguanide compound, CHET3, as a highly selective allosteric activator for TASK-3-containing K2P channels, including TASK-3 homomers and TASK-3/TASK-1 heteromers. CHET3 displayed potent analgesic effects in vivo in a variety of acute and chronic pain models in rodents that could be abolished pharmacologically or by genetic ablation of TASK-3. We further found that TASK-3-containing channels anatomically define a unique population of small-sized, transient receptor potential cation channel subfamily M member 8 (TRPM8)-, transient receptor potential cation channel subfamily V member 1 (TRPV1)-, or tyrosine hydroxylase (TH)-positive nociceptive sensory neurons and functionally regulate their membrane excitability, supporting CHET3 analgesic effects in thermal hyperalgesia and mechanical allodynia under chronic pain. Overall, our proof-of-concept study reveals TASK-3-containing K2P channels as a druggable target for treating pain.

The Role of Spinal GABAB Receptors in Cancer-Induced Bone Pain in Rats.

Cancer-induced bone pain (CIBP) remains a major challenge in advanced cancer patients because of our lack of understanding of its mechanisms. Previous studies have shown the vital role of γ-aminobutyric acid B receptors (GABABRs) in regulating nociception and various neuropathic pain models have shown diminished activity of GABABRs. However, the role of spinal GABABRs in CIBP remains largely unknown. In this study, we investigated the specific cellular mechanisms of GABABRs in the development and maintenance of CIBP in rats. Our behavioral results show that acute as well as chronic intrathecal treatment with baclofen, a GABABR agonist, significantly attenuated CIBP-induced mechanical allodynia and ambulatory pain. The expression levels of GABABRs were significantly decreased in a time-dependent manner and colocalized mostly with neurons and a minority with astrocytes and microglia. Chronic treatment with baclofen restored the expression of GABABRs and markedly inhibited the activation of cyclic adenosine monophosphate (cAMP)-dependent protein kinase and the cAMP-response element-binding protein signaling pathway. PERSPECTIVE: Our findings provide, to our knowledge, the first evidence that downregulation of GABABRs contribute to the development and maintenance of CIBP and restored diminished GABABRs attenuate CIBP-induced pain behaviors at least partially by inhibiting the protein kinase/cAMP-response element-binding protein signaling pathway. Therefore, spinal GABABR may become a potential therapeutic target for the management of CIBP.

STAT1 as a downstream mediator of ERK signaling contributes to bone cancer pain by regulating MHC II expression in spinal microglia.

Major histocompatibility class II (MHC II)-specific activation of CD4+ T helper cells generates specific and persistent adaptive immunity against tumors. Emerging evidence demonstrates that MHC II is also involved in basic pain perception; however, little is known regarding its role in the development of cancer-induced bone pain (CIBP). In this study, we demonstrate that MHC II expression was markedly induced on the spinal microglia of CIBP rats in response to STAT1 phosphorylation. Mechanical allodynia was ameliorated by either pharmacological or genetic inhibition of MHC II upregulation, which was also attenuated by the inhibition of pSTAT1 and pERK but was deteriorated by intrathecal injection of IFNγ. Furthermore, inhibition of ERK signaling decreased the phosphorylation of STAT1, as well as the production of MHC II in vivo and in vitro. These findings suggest that STAT1 contributes to bone cancer pain as a downstream mediator of ERK signaling by regulating MHC II expression in spinal microglia.

Minocycline attenuates bone cancer pain in rats by inhibiting NF-κB in spinal astrocytes.

AIM: To investigate the mechanisms underlying the anti-nociceptive effect of minocycline on bone cancer pain (BCP) in rats. METHODS: A rat model of BCP was established by inoculating Walker 256 mammary carcinoma cells into tibial medullary canal. Two weeks later, the rats were injected with minocycline (50, 100 µg, intrathecally; or 40, 80 mg/kg, ip) twice daily for 3 consecutive days. Mechanical paw withdrawal threshold (PWT) was used to assess pain behavior. After the rats were euthanized, spinal cords were harvested for immunoblotting analyses. The effects of minocycline on NF-κB activation were also examined in primary rat astrocytes stimulated with IL-1ß in vitro. RESULTS: BCP rats had marked bone destruction, and showed mechanical tactile allodynia on d 7 and d 14 after the operation. Intrathecal injection of minocycline (100 µg) or intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced mechanical tactile allodynia. Furthermore, intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced upregulation of GFAP (astrocyte marker) and PSD95 in spinal cord. Moreover, intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced upregulation of NF-κB, p-IKKα and IκBα in spinal cord. In IL-1ß-stimulated primary rat astrocytes, pretreatment with minocycline (75, 100 µmol/L) significantly inhibited the translocation of NF-κB to nucleus. CONCLUSION: Minocycline effectively alleviates BCP by inhibiting the NF-κB signaling pathway in spinal astrocytes.

Activation of PI3Kγ/Akt pathway mediates bone cancer pain in rats.

Bone cancer pain (BCP) is one of the most common and severe complications in patients suffering from primary bone cancer or metastatic bone cancer such as breast, prostate, or lung, which profoundly compromises their quality of life. Emerging lines of evidence indicate that central sensitization is required for the development and maintenance of BCP. However, the underlying mechanisms are largely unknown. In this study, we investigated the role of PI3Kγ/Akt in the central sensitization in rats with tumor cell implantation in the tibia, a widely used model of BCP. Our results showed that PI3Kγ and its downstream target pAkt were up-regulated in a time-dependent manner and distributed predominately in the superficial layers of the spinal dorsal horn neurons, astrocytes and a minority of microglia, and were colocalized with non-peptidergic, calcitonin gene-related peptide-peptidergic, and A-type neurons in dorsal root ganglion ipsilateral to tumor cell inoculation in rats. Inhibition of spinal PI3Kγ suppressed BCP-associated behaviors and the up-regulation of pAkt in the spinal cord and dorsal root ganglion. This study suggests that PI3Kγ/Akt signal pathway mediates BCP in rats. Central sensitization is required for the development and maintenance of bone cancer pain (BCP). In this study, we reported that PI3Kγ/Akt mediated the function of ephrinBs/EphBs in the central sensitization under BCP condition, and inhibition of spinal PI3Kγ suppressed BCP-associated behaviors. Our results suggest that inhibition of PI3Kγ/Akt may be a new target for the treatment of BCP.

Activation of spinal chemokine receptor CXCR3 mediates bone cancer pain through an Akt-ERK crosstalk pathway in rats.

Previously, we showed that activation of the spinal CXCL9, 10/CXCR3 pathway mediated bone cancer pain (BCP) in rats. However, the cellular mechanism involved is poorly understood. Here, we found that the activated CXCR3 was co-localized with either neurons, microglia, and astrocytes in the spinal cord, or non-peptidergic-, peptidergic-, and A-type neurons in the dorsal root ganglion. The inoculation of Walker-256 mammary gland carcinoma cells into the rat's tibia induced a time-dependent phosphorylation of Akt and extracellular signal-regulated kinase (ERK1/2) in the spinal cord, and CXCR3 was necessary for the phosphorylation of Akt and ERK 1/2. Meanwhile, CXCR3 was co-localized with either pAkt or pERK1/2. Blockage of either Akt or ERK1/2 prevented or reversed the mechanical allodynia in BCP rats. Furthermore, there was cross-activation between PI3K/Akt and Raf/MEK/ERK pathway under the BCP condition. Our results demonstrated that the activation of spinal chemokine receptor CXCR3 mediated BCP through Akt and ERK 1/2 kinase, and also indicated a crosstalk between PI3K/Akt and Raf/MEK/ERK signaling pathways under the BCP condition.