TRPM4 blocking antibody reduces neuronal excitotoxicity by specifically inhibiting glutamate-induced calcium influx under chronic hypoxia.

Excitotoxicity arises from unusually excessive activation of excitatory amino acid receptors such as glutamate receptors. Following an energy crisis, excitotoxicity is a major cause for neuronal death in neurological disorders. Many glutamate antagonists have been examined for their efficacy in mitigating excitotoxicity, but failed to generate beneficial outcome due to their side effects on healthy neurons where glutamate receptors are also blocked. In this study, we found that during chronic hypoxia there is upregulation and activation of a nonselective cation channel TRPM4 that contributes to the depolarized neuronal membrane potential and enhanced glutamate-induced calcium entry. TRPM4 is involved in modulating neuronal membrane excitability and calcium signaling, with a complex and multifaceted role in the brain. Here, we inhibited TRPM4 using a newly developed blocking antibody M4P, which could repolarize the resting membrane potential and ameliorate calcium influx upon glutamate stimulation. Importantly, M4P did not affect the functions of healthy neurons as the activity of TRPM4 channel is not upregulated under normoxia. Using a rat model of chronic hypoxia with both common carotid arteries occluded, we found that M4P treatment could reduce apoptosis in the neurons within the hippocampus, attenuate long-term potentiation impairment and improve the functions of learning and memory in this rat model. With specificity to hypoxic neurons, TRPM4 blocking antibody can be a novel way of controlling excitotoxicity with minimal side effects that are common among direct blockers of glutamate receptors.

Role of Brain Derived Neurotrophic Factor and Related Therapeutic Strategies in Central Post-Stroke Pain.

Brain-derived neurotrophic factor (BDNF) is vital for synaptic plasticity, cell persistence, and neuronal development in peripheral and central nervous systems (CNS). Numerous intracellular signalling pathways involving BDNF are well recognized to affect neurogenesis, synaptic function, cell viability, and cognitive function, which in turn affects pathological and physiological aspects of neurons. Stroke has a significant psycho-socioeconomic impact globally. Central post-stroke pain (CPSP), also known as a type of chronic neuropathic pain, is caused by injury to the CNS following a stroke, specifically damage to the somatosensory system. BDNF regulates a broad range of functions directly or via its biologically active isoforms, regulating multiple signalling pathways through interactions with different types of receptors. BDNF has been shown to play a major role in facilitating neuroplasticity during post-stroke recovery and a pro-nociceptive role in pain development in the nervous system. BDNF-tyrosine kinase receptors B (TrkB) pathway promotes neurite outgrowth, neurogenesis, and the prevention of apoptosis, which helps in stroke recovery. Meanwhile, BDNF overexpression plays a role in CPSP via the activation of purinergic receptors P2X4R and P2X7R. The neuronal hyperexcitability that causes CPSP is linked with BDNF-TrkB interactions, changes in ion channels and inflammatory reactions. This review provides an overview of BDNF synthesis, interactions with certain receptors, and potential functions in regulating signalling pathways associated with stroke and CPSP. The pathophysiological mechanisms underlying CPSP, the role of BDNF in CPSP, and the challenges and current treatment strategies targeting BDNF are also discussed.

Disrupting cortical astrocyte Ca2+ signaling in developing brain induces social deficits and depressive-like behaviors.

Astrocytes are present throughout the central nervous system and display complex intracellular Ca2+ signals. However, it is largely unknown regarding how astrocytic Ca2+ signals regulate neural microcircuits in developing brain and mammalian behavior in vivo. In this study, we specifically overexpressed the plasma membrane calcium-transporting ATPase2 (PMCA2) of cortical astrocytes and used immunohistochemistry, Ca2+ imaging, electrophysiology, and behavioral tests to investigate the effects of genetically reducing cortical astrocyte Ca2+ signaling during a critical developmental period in vivo. We found that reducing cortical astrocyte Ca2+ signaling during development led to social interaction deficits, depressive-like behaviors, and abnormal synaptic structure and transmission. In addition, restoring cortical astrocyte Ca2+ signaling using chemogenetic activation of Gq-coupled designer receptors exclusively activated by designer drugs rescued these synaptic and behavioral deficits. Together, our data demonstrate that the integrity of cortical astrocyte Ca2+ signaling in developing mice is critical for neural circuit development and may be involved in the pathogenesis of developmental neuropsychiatric diseases, such as autism spectrum disorders and depression.

Etomidate-Induced Myoclonus in Sprague-Dawley Rats Involves Neocortical Glutamate Accumulation and N -Methyl- d -Aspartate Receptor Activity.

BACKGROUND: Etomidate-induced myoclonus, a seizure-like movement, is of interest to anesthetists. However, its origin in the brain and its underlying mechanism remain unclear. METHODS: Adult male Sprague-Dawley rats were anesthetized with etomidate, propofol, or lidocaine plus etomidate. We assessed the incidence of myoclonus, behavioral scores, and levels of glutamate and γ-aminobutyric acid (GABA) in the neocortex and hippocampus. To determine the origin and how N -methyl- d -aspartate receptors (NMDARs) modulate etomidate-induced neuroexcitability, the local field potential and muscular tension were monitored. Calcium imaging in vitro and immunoblotting in vivo were conducted to investigate the mechanisms underlying myoclonus. RESULTS: The incidence of etomidate (1.5 mg/kg in vivo)-induced myoclonus was higher than that of propofol (90% vs 10%, P = .0010) and lidocaine plus etomidate (90% vs 20%, P = .0050). Etomidate at doses of 3.75 and 6 mg/kg decreased the mean behavioral score at 1 (mean difference [MD]: 1.80, 95% confidence interval [CI], 0.58-3.02; P = .0058 for both), 2 (MD: 1.60, 95% CI, 0.43-2.77; P = .0084 and MD: 1.70, 95% CI, 0.54-2.86; P = .0060), 3 (MD: 1.60, 95% CI, 0.35-2.85; P = .0127 and MD: 1.70, 95% CI, 0.46-2.94; P = .0091) minutes after administration compared to etomidate at a dose of 1.5 mg/kg. In addition, 0.5 and 1 µM etomidate in vitro increased neocortical intracellular calcium signaling; this signaling decreased when the concentration increased to 5 and 10 µM. Etomidate increased the glutamate level compared to propofol (mean rank difference: 18.20; P = .003), and lidocaine plus etomidate (mean rank difference: 21.70; P = .0002). Etomidate in vivo activated neocortical ripple waves and was positively correlated with muscular tension amplitude (Spearman's r = 0.785, P < .0001). Etomidate at 1.5 mg/kg decreased the K-Cl cotransporter isoform 2 (KCC2) level compared with propofol (MD: -1.15, 95% CI, -1.47 to -0.83; P < .0001) and lidocaine plus etomidate (MD: -0.64, 95% CI, -0.96 to -0.32; P = .0002), DL-2-amino-5-phosphopentanoic acid (AP5) suppressed these effects, while NMDA enhanced them. CONCLUSIONS: Etomidate-induced myoclonus or neuroexcitability is concentration dependent. Etomidate-induced myoclonus originates in the neocortex. The underlying mechanism involves neocortical glutamate accumulation and NMDAR modulation and myoclonus correlates with NMDAR-induced downregulation of KCC2 protein expression.

A combination of organic fertilizers partially substitution with alternate wet and dry irrigation could further reduce greenhouse gases emission in rice field.

Alternate wet and dry (AWD) irrigation and organic fertilizers substitution (OFS) have contrasting effects on CH4 and N2O emissions in rice cultivation. Combining these two practices may be feasible for simultaneous reduction of CH4 and N2O emission from paddy. Hence, we conducted a two-year field experiment to explore the reduction of greenhouse gases under the combination of AWD and OFS. The field experiment which was designed with two irrigation methods (continuous flooding (CF) irrigation and AWD irrigation), and five nitrogen regimes (N0, N135, and N180 represent 0, 135, and 180 kg N ha-1, respectively, ON25 and ON50 represent 25% and 50% OFS for inorganic fertilizer, respectively). The results showed a single-peak emission for CH4 fluxes during the whole rice growing season in all water and nitrogen treatments while the N2O fluxes peak only observed during tillering period with AWD irrigation. AWD irrigation and OFS showed a limited reduction in global warming potential (GWP). These were owing to that AWD irrigation reduced 38.3% CH4 emissions while increase 145.9% N2O emissions when compared to CF irrigation, and the low rate (25%) OFS only reduced CH4 emission by 29.4% while high rate (50%) only reduce N2O emission by 38.8% when compared to conventional inorganic nitrogen fertilizer (N180). Combined AWD and ON25 could maximize the reduction in GWP and yield-scaled GWP, which were reduce 58.0% and 52.5%, respectively, compare to the conventional water and nitrogen management (CF and N180). Furthermore, the structural equation modelling (SEM) indicated that the soil dissolved organic carbon (DOC) and rice aboveground biomass showed a significant positive effect on CH4 fluxes while soil NH4+ with a negative effect, and the soil NH4+, nitrification potential, denitrification potential significant affected N2O fluxes with a positive effect while DOC with a negative effect. These results investigated that 25% OFS rate for inorganic fertilizer could further reduce warming potential in AWD irrigation rice field.

Effects of biochar on rice yield, grain quality and starch viscosity attributes.

BACKGROUND: Biochar can play a key role in improving paddy soil and productivity. However, there is limited information on the effects of biochar on rice quality and starch gelatinization. In this study, four rice straw biochar dosage treatments (0, 20, 40 and 60 g kg-1 ; CK, C20, C40 and C60, respectively) were set up to investigate rice yield components, rice processing, appearance and cooking quality, and starch gelatinization. RESULTS: Addition of biochar increased the effective panicle, grain number per panicle and seed setting rate. However, it decreased the 1000-grain weight, resulting in an increase in yield. In 2019, all the biochar treatments improved the head rice rate (9.13-11.42%), whereas in 2020 only the C20 treatment improved. Low biochar dosage had little effect on grain appearance. High biochar dosage significantly decreased the chalky rice rate by 21.47% and chalkiness by 19.44% in 2019. However, it significantly increased the chalky rice rate and chalkiness by 118.95% and 85.45% in 2020, respectively. Biochar significantly lowered the amylose content except for the C20 and C40 treatments in 2020, and the gel consistency. The C40 and C60 treatments significantly increased the peak and breakdown viscosities and decreased the setback viscosity compared with CK. Correlation analysis showed that starch gelatinization characteristics were significantly correlated with the head rice rate, chalky rate and amylose content. CONCLUSION: A lower biochar dosage can improve the yield and milled rice rate and maintain a higher quality of appearance, whereas a higher biochar dosage can significantly improve starch gelatinization. © 2023 Society of Chemical Industry.

Astroglial dysfunctions drive aberrant synaptogenesis and social behavioral deficits in mice with neonatal exposure to lengthy general anesthesia.

Lengthy use of general anesthetics (GAs) causes neurobehavioral deficits in the developing brain, which has raised significant clinical concerns such that the United States Food and Drug Administration (FDA) is warning on the use of GAs in children younger than 3 years. However, the molecular and cellular mechanisms for GAs-induced neurotoxicity remain largely unknown. Here, we report that sevoflurane (Sevo), a commonly used GA in pediatrics, caused compromised astrocyte morphogenesis spatiotemporally correlated to synaptic overgrowth, with reduced synaptic function in developing cortex in a regional-, exposure-length-, and age-specific manner. Sevo disrupted astrocyte Ca2+ homeostasis both acutely and chronically, which led to the down-regulation of Ezrin, an actin-binding membrane-bound protein, which we found was critically involved in astrocyte morphogenesis in vivo. Importantly, overexpression of astrocyte Ezrin rescued astrocytic and neuronal dysfunctions and fully corrected deficits in social behaviors in developing mice with lengthy Sevo exposure. Our data uncover that, in addition to neurons, astrocytes may represent important targets for GAs to exert toxic effects and that astrocyte morphological integrity is crucial for synaptogenesis and neurological behaviors.

Oncotic Cell Death in Stroke.

Oncotic cell death or oncosis represents a major mechanism of cell death in ischaemic stroke, occurring in many central nervous system (CNS) cell types including neurons, glia and vascular endothelial cells. In stroke, energy depletion causes ionic pump failure and disrupts ionic homeostasis. Imbalance between the influx of Na+ and Cl- ions and the efflux of K+ ions through various channel proteins and transporters creates a transmembrane osmotic gradient, with ensuing movement of water into the cells, resulting in cell swelling and oncosis. Oncosis is a key mediator of cerebral oedema in ischaemic stroke, contributing directly through cytotoxic oedema, and indirectly through vasogenic oedema by causing vascular endothelial cell death and disruption of the blood-brain barrier (BBB). Hence, inhibition of uncontrolled ionic flux represents a novel and powerful strategy in achieving neuroprotection in stroke. In this review, we provide an overview of oncotic cell death in the pathology of stroke. Importantly, we summarised the therapeutically significant pathways of water, Na+, Cl- and K+ movement across cell membranes in the CNS and their respective roles in the pathobiology of stroke.

Comparison of outcomes of hysteroscopic myomectomy of type 2 submucous fibroids greater than 4 cm in diameter via pretreatment with HIFU or GnRH-a.

OBJECTIVE: To compare the efficacy and safety of high-intensity focused ultrasound (HIFU) and gonadotropin-releasing analogues (GnRH-a) as pretreatments for the hysteroscopic transcervical resection of myoma (TCRM) for type 2 submucosal fibroids greater than 4 centimeters in diameter. MATERIALS AND METHODS: Seventy-nine patients were assigned into two groups according patient preference: 42 in HIFU and 37 in GnRHa. TCRM was performed after 3 months of pretreatment with HIFU or GnRHa. RESULTS: Following pretreatment with HIFU or GnRHa, uterine-fibroid symptom (UFS) scores and hemoglobin levels (HGB) showed improvement. The fibroid maximum diameter, size of fibroids, and volume of the uterus were decreased. Following HIFU pretreatment, one case reported complete vaginal fibroid expulsion, and four reported partial fibroid expulsion. No similar cases were found in the GnRHa group. Eighteen patients were lost to follow-up prior to TCRM. Among the 31 patients in HIFU, the fibroids were downgraded to type 0 in 10 cases and type 1 in 5 cases. Of the 30 patients in GnRHa, the treated fibroids were downgraded to type 1 in 9 cases. The mean operation time and intraoperative blood loss of the HIFU group were significantly lower than those in the GnRHa group. No significant differences were observed in the incidence of intraoperative complications and the one-time resection rate of fibroids between the two groups (p>.05). CONCLUSIONS: HIFU seems to be superior to GnRHa as a pretreatment method prior to TCRM for type 2 submucosal fibroids greater than 4 centimeters in diameter.

Differences and Correlation Analysis of Birth Weight and Overweight/Obesity in Shanghai Twin Cohort.

The objective of this study was to analyze differences in birth weight and overweight/obesity in a Shanghai twin cohort. We also wanted to study their association and explore possible risk factors for the discordance of overweight/obesity within twins. This was an internal case-control study designed for twins. The 2012 Shanghai Twin Registration System baseline survey data of a total of 3417 twin pairs were statistically analyzed using SPSS22 software. Results show that the body mass index (BMI) of the Shanghai twin population increased with age. Twins with a high birth weight had a higher BMI and a higher rate of overweight and obesity; 0- to 6-year-old twins, male twins and dizygotic (DZ) twins had higher rates of overweight/obesity than other groups. The greater the discordant birth weight rate of twins, the more obvious the difference in BMI (p < .05). There was a significant difference in overweight/obesity between twins with a relative difference of birth weight ≥15% in DZ twins (p < .05). DZ twins, male twins and 0- to 6-year-old twins were more likely to be discordant in overweight/obese than others. The discordant birth weight within twins was not a risk factor for discordant overweight/obesity. However, attention should be paid to childhood obesity, and appropriate interventions should be made at the appropriate time. Genetics may play an important role in the occurrence and development of overweight/obesity. In conclusion, discordant growth and development in the uterus early in life may not lead to discordant weight development in the future.

Contribution of Neuronal and Glial Two-Pore-Domain Potassium Channels in Health and Neurological Disorders.

Two-pore-domain potassium (K2P) channels are widespread in the nervous system and play a critical role in maintaining membrane potential in neurons and glia. They have been implicated in many stress-relevant neurological disorders, including pain, sleep disorder, epilepsy, ischemia, and depression. K2P channels give rise to leaky K+ currents, which stabilize cellular membrane potential and regulate cellular excitability. A range of natural and chemical effectors, including temperature, pressure, pH, phospholipids, and intracellular signaling molecules, substantially modulate the activity of K2P channels. In this review, we summarize the contribution of K2P channels to neuronal excitability and to potassium homeostasis in glia. We describe recently discovered functions of K2P channels in glia, such as astrocytic passive conductance and glutamate release, microglial surveillance, and myelin generation by oligodendrocytes. We also discuss the potential role of glial K2P channels in neurological disorders. In the end, we discuss current limitations in K2P channel researches and suggest directions for future studies.

A General Strategy to Design Highly Fluorogenic Far-Red and Near-Infrared Tetrazine Bioorthogonal Probes.

Highly fluorogenic tetrazine bioorthogonal probes emitting at near-infrared wavelengths are in strong demand for biomedical imaging applications. Herein, we have developed a strategy for forming a palette of novel Huaxi-Fluor probes in situ, whose fluorescence increases hundreds of times upon forming the bioorthogonal reaction product, pyridazine. The resulting probes show large Stokes shifts and high quantum yields. Manipulating the conjugate length and pull-push strength in the fluorophore skeleton allows the emission wavelength to be fine-tuned from 556 to 728 nm. The highly photo-stable and biocompatible probes are suitable for visualizing organelles in live cells without a washing step and for imaging of tumors in live small animals to depths of 500 µm by two-photon excitation.

Brain-derived neurotrophic factor and post-stroke depression.

Brain-derived neurotrophic factor (BDNF) is well known to play a critical role in cognition. Its role in mood disorders, including post stroke depression (PSD), is also recognized with more evidence surfacing. In patients with PSD, their serum BNDF level is lower than in those without depression. Furthermore, antidepressants could enhance BDNF expression in the brain, resulting in an alleviation of depression symptoms. Such therapeutic effect can be abolished in animals with the BDNF gene deleted. In PSD patients, the presence of stroke may contribute to the development of depression, including affecting the expression of BDNF. However, the mechanisms of BDNF in the development of PSD remain largely unknown. Lower BDNF levels may have existed in some patients before stroke onset, making them vulnerable to develop depressive symptoms. Meanwhile, the hypoxic environment induced by stroke could possibly downregulate BDNF expression in the brain. Current antidepressant treatments are not specific for PSD and there is a lack of treatments to address the linkage between stroke and PSD. This review summarizes the current knowledge of BDNF in PSD. By regulating BDNF expression, a synergistic effect may be achieved when such treatments are applied together with existing antidepressants.

Exclusion of alternative exon 33 of CaV1.2 calcium channels in heart is proarrhythmogenic.

Alternative splicing changes the CaV1.2 calcium channel electrophysiological property, but the in vivo significance of such altered channel function is lacking. Structure-function studies of heterologously expressed CaV1.2 channels could not recapitulate channel function in the native milieu of the cardiomyocyte. To address this gap in knowledge, we investigated the role of alternative exon 33 of the CaV1.2 calcium channel in heart function. Exclusion of exon 33 in CaV1.2 channels has been reported to shift the activation potential -10.4 mV to the hyperpolarized direction, and increased expression of CaV1.2Δ33 channels was observed in rat myocardial infarcted hearts. However, how a change in CaV1.2 channel electrophysiological property, due to alternative splicing, might affect cardiac function in vivo is unknown. To address these questions, we generated mCacna1c exon 33-/--null mice. These mice contained CaV1.2Δ33 channels with a gain-of-function that included conduction of larger currents that reflects a shift in voltage dependence and a modest increase in single-channel open probability. This altered channel property underscored the development of ventricular arrhythmia, which is reflected in significantly more deaths of exon 33-/- mice from ß-adrenergic stimulation. In vivo telemetric recordings also confirmed increased frequencies in premature ventricular contractions, tachycardia, and lengthened QT interval. Taken together, the significant decrease or absence of exon 33-containing CaV1.2 channels is potentially proarrhythmic in the heart. Of clinical relevance, human ischemic and dilated cardiomyopathy hearts showed increased inclusion of exon 33. However, the possible role that inclusion of exon 33 in CaV1.2 channels may play in the pathogenesis of human heart failure remains unclear.

[The Effect of miR-503-5p on the Proliferation, Invasion, Migration and Epithelial Interstitium of Cervical Cancer HeLa Cells via Targeting E2 F3].

OBJECTIVE: To investigate the effect of miR-503-5p on the proliferation, invasion, migration and epithelialization of cervical cancer HeLa cells via targeting E2 F3. METHODS: Four ccervical cancer HeLa cells groups were set up including control group, mimic-NC group, miR-503-5p mimic group, E2 F3 group, miR-503-5p mimic+ E2 F3 group (mimic+ E2 F3 group). The plasmids were separately or jointly transinfected into cervical cancer Hela cells of each group by Lipofectamine 2000, After transinfection, the target gene was predicted by gene prediction software, the targeting relationship was verified by fluorescein experiment, the expression of miR-503-5p and E2 F3 was detected by RT-PCR, cell proliferation was detected by MTT assay, expression of Ki67, proliferating cell nuclear antigen (PCNA), E-cadherin and N-cadherin were detected by Western blot, cell invasion was detected by Transwell, and cell migration was detected by scratch test. Nude mice were divided into control group and miR-503-5p mimic group, and 0.2 mL of cervical cancer HeLa cell suspension transfected with mimic-NC or miR-503-5p mimic was injected subcutaneously into the ventral side of the right hind limb of nude mice. Thirty days post injection, the nude mice were sacrificed by cervical dislocation. The tumor weight was weighed by an electronic balance, and the expression of KI67 and Vimentin in the tumor tissue was detected by immunohistochemistry. RESULTS: The expression level of miR-503-5p in cervical cancer HeLa cells was down-regulated, miR-503-5p directly targeted E2 F3 by binding with E2 F3 at binding sites in the 3'UTR region. Over-expressing of miR-503-5p inhibited the expression of E2 F3, significantly decreased cell growth rate and the expression level of Ki67 and PCNA, decreased the number of invasive cells, widened the scratches, reduced the healing rate, up-regulated the expression of E-cadherin and also down-regulated the expression of N-cadherin ( P<0.01). Over-expressing of miR-503-5p significantly reduced the volume and weight of transplanted tumors, and decreased the proportion of positive Ki67 and Vimentin ( P<0.01). CONCLUSION: miR-503-5p inhibits the proliferation, invasion, migration and epithelialization of cervical cancer HeLa cells by targeting E2 F3.

Regulation of Blood Pressure by Targeting CaV1.2-Galectin-1 Protein Interaction.

BACKGROUND: L-type CaV1.2 channels play crucial roles in the regulation of blood pressure. Galectin-1 (Gal-1) has been reported to bind to the I-II loop of CaV1.2 channels to reduce their current density. However, the mechanistic understanding for the downregulation of CaV1.2 channels by Gal-1 and whether Gal-1 plays a direct role in blood pressure regulation remain unclear. METHODS: In vitro experiments involving coimmunoprecipitation, Western blot, patch-clamp recordings, immunohistochemistry, and pressure myography were used to evaluate the molecular mechanisms by which Gal-1 downregulates CaV1.2 channel in transfected, human embryonic kidney 293 cells, smooth muscle cells, arteries from Lgasl1-/- mice, rat, and human patients. In vivo experiments involving the delivery of Tat-e9c peptide and AAV5-Gal-1 into rats were performed to investigate the effect of targeting CaV1.2-Gal-1 interaction on blood pressure monitored by tail-cuff or telemetry methods. RESULTS: Our study reveals that Gal-1 is a key regulator for proteasomal degradation of CaV1.2 channels. Gal-1 competed allosterically with the CaVß subunit for binding to the I-II loop of the CaV1.2 channel. This competitive disruption of CaVß binding led to CaV1.2 degradation by exposing the channels to polyubiquitination. It is notable that we demonstrated that the inverse relationship of reduced Gal-1 and increased CaV1.2 protein levels in arteries was associated with hypertension in hypertensive rats and patients, and Gal-1 deficiency induces higher blood pressure in mice because of the upregulated CaV1.2 protein level in arteries. To directly regulate blood pressure by targeting the CaV1.2-Gal-1 interaction, we administered Tat-e9c, a peptide that competed for binding of Gal-1 by a miniosmotic pump, and this specific disruption of CaV1.2-Gal-1 coupling increased smooth muscle CaV1.2 currents, induced larger arterial contraction, and caused hypertension in rats. In contrasting experiments, overexpression of Gal-1 in smooth muscle by a single bolus of AAV5-Gal-1 significantly reduced blood pressure in spontaneously hypertensive rats. CONCLUSIONS: We have defined molecularly that Gal-1 promotes CaV1.2 degradation by replacing CaVß and thereby exposing specific lysines for polyubiquitination and by masking I-II loop endoplasmic reticulum export signals. This mechanistic understanding provided the basis for targeting CaV1.2-Gal-1 interaction to demonstrate clearly the modulatory role that Gal-1 plays in regulating blood pressure, and offering a potential approach for therapeutic management of hypertension.

TRPM4-specific blocking antibody attenuates reperfusion injury in a rat model of stroke.

Reperfusion therapy is currently the gold standard treatment for acute ischemic stroke. However, reperfusion injuries such as oedema and haemorrhagic transformation largely limit the use of this potent treatment to a narrow time window. Recently, transient receptor potential melastatin 4 (TRPM4) channel has emerged as a potential target for vascular protection in stroke management. Non-specificity and side effects are major concerns for current TRPM4 blockers. The present study was undertaken to develop a novel TRPM4 blocker for stroke management. We report the generation of a TRPM4-specific antibody M4P which binds to a region close to the channel pore. M4P could inhibit TRPM4 current and downregulate TRPM4 surface expression, therefore prevent hypoxia-induced cell swelling. In the rat model of 3-h stroke reperfusion, application of M4P at 2 h after occlusion ameliorated reperfusion injury by improving blood-brain barrier integrity, and enhanced functional recovery. Our results demonstrate that TRPM4 blockade could attenuate reperfusion injury in stroke recanalization. When applied together with reperfusion treatments, TRPM4 blocking antibody has the potential to extend the therapeutic time window for acute ischemic stroke.

Studies on the relationship between perforating vein insufficiency and iliac compression syndrome.

OBJECTIVE: To study correlation among number(n), diameter (D), and blood reflux time(t) and the left common iliac vein stenosis degree of the expansion of perforating veins, so as to guide the clinical formulation and adjust the treatment plan. METHODS: Retrospective analysis of 45 PVs patients with left common iliac vein in different degrees of compression in our hospital from 2010 to 2012 was performed. Left common iliac vein was divided into 50%-69%, 70%-99%, 30%-49% and occlusion of the stenosis to avoid the error of the left iliac vein stenosis. Pearson's correlation analysis among the number, diameter, and blood reflux time of perforating veins and left common iliac vein was performed. RESULTS: Pearson's correlation analysis among the number, diameter, and blood back flow time of perforating veins, and the degree of stenosis was performed, and these results showed that correlation coefficients among the number, diameter, and blood return the PVs between flow time and the degree of stenosis were rp-n = 0.784, rp-d = 0.893, rp-t = 0.845 (P < .001), respectively. The two variables exist positive correlation and correlation was significant. CONCLUSION: With the increase in left common iliac vein stenosis, the number of perforating veins and the diameter increased, and the time of blood flow were prolonged.

Synthesis of 2-morpholinetetraphenylporphyrins and their photodynamic activities.

A series of 2-morpholinetetraphenylporphyrins functionalized with various substituents (Cl, Me, MeO group) at 4-phenyl position were prepared via nucleophilic substitution of 2-nitroporphyrin copper derivatives with morpholine by refluxing under a nitrogen atmosphere and then demetalization. Their basic photophysical properties, intracellular localization, cytotoxicities in vitro and in vivo were also investigated. All synthesized photosensitizers exhibited longer maxima absorption wavelengths than Hematoporphyrin monomethyl ether (HMME). They showed low dark cytotoxicity compared with that of HMME and were more phototoxic than HMME against Eca-109 cells in vitro. M3 also exhibited better photodynamic antitumor efficacy on BALB/c nude mice at a lower concentration. Therefore, M3 is a promising antitumor photosensitizer in photodynamic therapy application.

Gypenoside XVII Prevents Atherosclerosis by Attenuating Endothelial Apoptosis and Oxidative Stress: Insight into the ERα-Mediated PI3K/Akt Pathway.

Phytoestrogens are estrogen-like compounds of plant origin. The pharmacological activities of phytoestrogens are predominantly due to their antioxidant, anti-inflammatory and lipid-lowering properties, which are mediated via the estrogen receptors (ERs): estrogen receptor alpha (ERα) and estrogen receptor beta (ERß) and possibly G protein-coupled estrogen receptor 1 (GPER). Gypenoside XVII (GP-17) is a phytoestrogen that is widely used to prevent cardiovascular disease, including atherosclerosis, but the mechanism underlying these therapeutic effects is largely unclear. This study aimed to assess the anti-atherogenic effects of GP-17 and its mechanisms in vivo and in vitro. In vivo experiments showed that GP-17 significantly decreased blood lipid levels, increased the expression of antioxidant enzymes and decreased atherosclerotic lesion size in ApoE-/- mice. In vitro experiments showed that GP-17 significantly prevented oxidized low-density lipoprotein (Ox-LDL)-induced endothelial injury. The underlying protective mechanisms of GP-17 were mediated by restoring the normal redox state, up-regulating of the ratio of Bcl-2 to Bax and inhibiting the expression of cleaved caspase-3 in Ox-LDL-induced human umbilical vein endothelial cell (HUVEC) injury. Notably, we found that GP-17 treatment predominantly up-regulated the expression of ERα but not ERß. However, similar to estrogen, the protective effect of GP-17 could be blocked by the ER antagonist ICI182780 and the phosphatidylinositol 3-kinase (PI3K) antagonist LY294002. Taken together, these results suggest that, due to its antioxidant properties, GP-17 could alleviate atherosclerosis via the ERα-mediated PI3K/Akt pathway.