Immediate breast reconstruction with laparoscopically harvested omental flap: A retrospective analysis with a maximum 12-year follow-up.

PURPOSE: To evaluate the clinical efficacy of immediate breast reconstruction with free or pedicled laparoscopically harvested omental flaps (LHOFs). METHODS: Between March 2011 and 2021, 82 patients who underwent immediate breast reconstruction with free or pediculated omental flaps were enrolled. Breast total or partial mastectomy, laparoscopic greater omentum harvest, and breast reconstruction were carried out in an orderly manner. Postoperative operative results, cosmetic outcomes, and complications were investigated. RESULTS: Seventeen cases of free LHOF and 65 cases of pedicled LHOF were performed. Cosmetic results were mostly satisfactory (61% excellent, 35% good), with a soft breast that was natural in appearance. Satisfaction investigation showed that 96.2% of patients were satisfied with the reconstructed breast. Uneventful follow-up showed no abdominal complications at the donor site, and the surface skin displayed no swelling. No major complications were found, except for three cases of necrosis. One patient developed slight hematoma. Two patients were found to have local recurrence, and one had distant metastasis. Twenty-four patients accepted radiotherapy, but no size reduction was noted after radiotherapy. We followed the patients to determine their survival status. All patients were alive, except for 1 in the free LHOF group who died 31.2 months after surgery. CONCLUSION: Immediate breast reconstruction with LHOF provides a soft reconstructed breast with relatively little donor-site deformity and is useful for breast tumor-specific immediate reconstruction.

[Effect and mechanism of leonurine on pressure overload-induced cardiac hypertrophy in rats].

To investigate the effects of leonurine(Leo) on abdominal aortic constriction(AAC)-induced cardiac hypertrophy in rats and its mechanism. A rat model of pressure overload-induced cardiac hypertrophy was established by AAC method. After 27-d intervention with high-dose(30 mg·kg~(-1)) and low-dose(15 mg·kg~(-1)) Leo or positive control drug losartan(5 mg·kg~(-1)), the cardiac function was evaluated by hemodynamic method, followed by the recording of left ventricular systolic pressure(LVSP), left ventricular end-diastolic pressure(LVESP), as well as the maximum rate of increase and decrease in left ventricular pressure(±dp/dt_(max)). The degree of left ventricular hypertrophy was assessed based on heart weight index(HWI) and left ventricular mass index(LVWI). Myocardial tissue changes and the myocardial cell diameter(MD) were measured after hematoxylin-eosin(HE) staining. The contents of angiotensin Ⅱ(AngⅡ) and angiotensin Ⅱ type 1 receptor(AT1 R) in myocardial tissue were detected by ELISA. The level of Ca~(2+) in myocardial tissue was determined by colorimetry. The protein expression levels of phospholipase C(PLC), inositol triphosphate(IP3), AngⅡ, and AT1 R were assayed by Western blot. Real-time quantitative PCR(qRT-PCR) was employed to determine the mRNA expression levels of ß-myosin heavy chain(ß-MHC), atrial natriuretic factor(ANF), AngⅡ, and AT1 R. Compared with the model group, Leo decreased the LVSP, LVEDP, HWI, LVWI and MD values, but increased ±dp/dt_(max) of the left ventricle. Meanwhile, it improved the pathological morphology of myocardial tissue, reduced cardiac hypertrophy, edema, and inflammatory cell infiltration, decreased the protein expression levels of PLC, IP3, AngⅡ, AT1 R, as well as the mRNA expression levels of ß-MHC, ANF, AngⅡ, AT1 R, c-fos, and c-Myc in myocardial tissue. Leo inhibited AAC-induced cardiac hypertrophy possibly by influencing the RAS system.

Design of Lubricant-Infused Surfaces Based on Mussel-Inspired Nanosilica Coatings: Solving Adhesion by Pre-Adhesion.

Slippery liquid-infused porous surfaces (SLIPSs) have attracted wide interest with regard to their excellent liquid repellency properties and broad applications in various fields associated with anti-adhesion. However, the preparation processes depending on the chemical properties of the substrate and the poor stability of the lubricant layer hinder the practical applications. In this work, a facile method to fabricate SLIPSs based on the mussel-inspired polydopamine (PDA)-mediated nanosilica structures is demonstrated. A variety of substrates can be decorated with SLIPSs by successive treatment of PDA-assisted sol-gel process, fluorination, and lubricant filling. The robust uniform and nanotextured silica coating, mediated by the pre-adhered PDA layer, shows enhanced lubricant-locking ability even when subjected to increased evaporation and high shear from flowing water or spinning compared with hierarchical silica rough structures. The obtained SLIPSs exhibit high transparency and excellent resistance against adhesion of liquid/solid contaminants and biofoulings through this pre-adhesion of PDA strategy. The well-defined nanosilica coating of high decoration covering micron-scaled pore walls enables improved durability of the slippery surfaces for antifouling of the porous membrane under pressure-driven filtration and this may be employed as a potential candidate for fouling resistance of porous materials.

Tanshinone IIA alleviates brain damage in a mouse model of neuromyelitis optica spectrum disorder by inducing neutrophil apoptosis.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD), an autoimmune astrocytopathic disease associated with the anti-aquaporin-4 (AQP4) antibody, is characterized by extensive necrotic lesions primarily located on the optic nerves and spinal cord. Tanshinone IIA (TSA), an active natural compound extracted from Salvia miltiorrhiza Bunge, has profound immunosuppressive effects on neutrophils. OBJECTIVE: The present study aimed to evaluate the effect of TSA on NMOSD mice and explore the underlying mechanisms. Mice were initially administered TSA (pre-TSA group, n = 20) or vehicle (vehicle group, n = 20) every 8 h for 3 days, and then NMOSD model was induced by intracerebral injection of NMOSD-immunoglobulin G (NMO-IgG) and human complement (hC). In addition, post-TSA mice (n = 10) were administered equal dose of TSA at 8 h and 16 h after model induction. At 24 h after intracerebral injection, histological analysis was performed to assess the inhibitory effects of TSA on astrocyte damage, demyelination, and neuroinflammation in NMOSD mice, and western blotting was conducted to clarify the effect of TSA on the NF-κB and MAPK signaling pathways. Furthermore, flow cytometry and western blotting were conducted to verify the proapoptotic effects of TSA on neutrophils in vitro. RESULTS: There was a profound reduction in astrocyte damage and demyelination in the pre-TSA group and post-TSA group. However, prophylactic administration of TSA induced a better effect than therapeutic treatment. The number of infiltrated neutrophils was also decreased in the lesions of NMOSD mice that were pretreated with TSA. We confirmed that prophylactic administration of TSA significantly promoted neutrophil apoptosis in NMOSD lesions in vivo, and this proapoptotic effect was mediated by modulating the caspase pathway in the presence of inflammatory stimuli in vitro. In addition, TSA restricted activation of the NF-κB signaling pathway in vivo. CONCLUSION: Our data provide evidence that TSA can act as a prophylactic agent that reduces NMO-IgG-induced damage in the mouse brain by enhancing the resolution of inflammation by inducing neutrophil apoptosis, and TSA may serve as a promising therapeutic agent for neutrophil-associated inflammatory disorders, such as NMOSD.

Multifloroside Suppressing Proliferation and Colony Formation, Inducing S Cell Cycle Arrest, ROS Production, and Increasing MMP in Human Epidermoid Carcinoma Cell Lines A431.

Multifloroside (4), together with 10-hydroxyoleoside 11-methyl ester (1), 10-hydroxyoleoside dimethyl ester (2), and 10-hydroxyligustroside (3), are all secoiridoids, which are naturally occurring compounds that possess a wide range of biological and pharmacological activities. However, the anti-cancer activity of 1-4 has not been evaluated yet. The objective of this work was to study the anti-cancer activities of 1-4 in the human epidermoid carcinoma cell lines A431 and the human non-small cell lung cancer (NSCLC) cell lines A549. The results indicate that 1-4 differ in potency in their ability to inhibit the proliferation of human A431 and A549 cells, and multifloroside (4) display the highest inhibitory activity against A431 cells. The structure-activity relationships suggest that the o-hydroxy-p-hydroxy-phenylethyl group may contribute to the anti-cancer activity against A431 cells. Multifloroside treatment can also inhibit cell colony formation, arrest the cell cycle in the S-phase, increase the levels of reactive-oxygen-species (ROS), and mitochondrial membrane potential (MMP), but it did not significantly induce cell apoptosis at low concentrations. The findings indicated that multifloroside (4) has the tendency to show selective anti-cancer effects in A431 cells, along with suppressing the colony formation, inducing S cell cycle arrest, ROS production, and increasing MMP.

Theoretical study of radiative and nonradiative decay rates for Cu(i) complexes with double heteroleptic ligands.

In this paper, we conducted DFT and TDDFT calculations on three double heteroleptic Cu(i) complexes to understand how different substituents on N^N ligands influence the phosphorescence quantum yield (PLQY). Both radiative and nonradiative decay processes were thoroughly investigated. Factors that determine the rate of radiative process (kr) were considered, including the lowest triplet excited state E(T1), the transition dipole moment MSm,j of the Sm → S0 transition, the spin-coupled matrix element SOC, and the singlet-triplet splitting energies ΔE(Sm-T1). The results indicate that E(T1), MSm,j and SOC increase and ΔE(Sm-T1) decreases upon introducing -Ph and -CH2- groups on the N^N ligands. The net results lead to a gradual increase of kr in the three Cu(i) complexes, from 1 (0.48 × 104 s-1) to 2 (0.64 × 104 s-1) and then to 3 (1.61 × 104 s-1). The rate of nonradiative decay process (knr) was computed by a convolution method. We explored how knr is determined by SOC between T1 and S0 states (T1|SOC|S02), effective energy gap ΔE' and the Huang-Rhys factor (S). We found that T1|SOC|S02 and ΔE' contribute significantly to knr, but S does not determine the order of knr. knr gradually decreases from complex 1 (2.51 × 106 s-1) to 2 (0.32 × 106 s-1) and then to 3 (0.14 × 106 s-1) after introducing -Ph and -CH2- groups on the N^N ligands. The computed PLQYs for the three complexes are 1: 0.0019, 2: 0.0198, and 3: 0.1011. These are quantitatively consistent with the experimental observation (1: 0.0028, 2: 0.0061, and 3: 0.1000).

Analytical Solutions for Multi-Time Scale Fractional Stochastic Differential Equations Driven by Fractional Brownian Motion and Their Applications.

In this paper, we investigate analytical solutions of multi-time scale fractional stochastic differential equations driven by fractional Brownian motions. We firstly decompose homogeneous multi-time scale fractional stochastic differential equations driven by fractional Brownian motions into independent differential subequations, and give their analytical solutions. Then, we use the variation of constant parameters to obtain the solutions of nonhomogeneous multi-time scale fractional stochastic differential equations driven by fractional Brownian motions. Finally, we give three examples to demonstrate the applicability of our obtained results.

Low expression of complement inhibitory protein CD59 contributes to humoral autoimmunity against astrocytes.

Neuromyelitis optica spectrum disorder is primarily an anti-aquaporin 4 autoantibody-mediated, central nervous system-restricted channelopathy. Patients frequently develop central nervous system-restricted lesions even though autoantigen aquaporin 4 in neuromyelitis optica spectrum disorder is broadly distributed in the central nervous system and peripheral organs. The cause of such tissue-specific immune response remains largely unknown. We confirmed here that CD59, an inhibitory regulator of the complement membrane attack complex, is expressed and co-localized with aquaporin 4 in peripheral organs but is only minimally expressed in astrocytes in the central nervous system. In addition, we further found that CD59 overexpression in mouse brains decreased demyelination, blocked the loss of astrocytes and aquaporin 4, and inhibited membrane attack complex formation and infiltration of inflammatory cells. Inactivation of CD59 in mouse peripheral aquaporin 4-expressing cells and tissues led to complement-dependent cytotoxicity. In accordance with the mouse data, human samples presented higher expression of CD59 in many aquaporin 4-expressing peripheral tissues but not in astrocytes. Silencing or blocking CD59 in aquaporin 4-expressing human tracheal epithelial and skeletal muscle cells induced membrane attack complex formation and cytotoxicity, which suggests a protective role of CD59 in anti-aquaporin 4 antibodies-mediated complement toxicity. Our findings suggest that low CD59 expression in astrocytes may contribute to central nervous system-restricted lesions in neuromyelitis optica spectrum disorder. Restoring CD59 expression in astrocytes may serve as a novel therapeutic target of neuromyelitis optica spectrum disorder.

Silencing IFN-γ binding/signaling in astrocytes versus microglia leads to opposite effects on central nervous system autoimmunity.

IFN-γ, the hallmark cytokine of Th1 cells, plays an important role in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Thus far, the role of IFN-γ in EAE has been largely studied through its effects on immune cells, whereas much less is known about its effects on CNS cells, especially in vivo. In this study, we dissected the in vivo effects and mechanisms of IFN-γ binding/signaling in astrocytes and microglia, and found that IFN-γ signaling in these cell types has opposite effects in EAE pathogenesis. Silencing IFN-γ binding/signaling in astrocytes alleviated EAE, whereas in microglia, and likely in some infiltrating macrophages, it increased disease severity. Silencing IFN-γ signaling in astrocytes resulted in diminished expression of chemokines and fewer inflammatory cells infiltrating into the CNS, whereas blocking IFN-γ binding/signaling in microglia, probably infiltrating macrophages as well, increased disease severity through augmented activation and proliferation of microglia. Further, blocking IFN-γ binding/signaling in astrocytes alleviated both Th1- and Th17-mediated adoptive EAE, indicating an important role for IFN-γ signaling in astrocytes in autoimmune CNS inflammation. Thus, our study defines novel mechanisms of action of IFN-γ in EAE pathogenesis, and also highlights an opportunity for development of multiple sclerosis therapies directed at CNS cells.

IL-9 signaling affects central nervous system resident cells during inflammatory stimuli.

Interleukin (IL) 9, a dominant cytokine in Th9 cells, has been proven to play a pathogenic role in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), by augmenting T cell activation and differentiation; however, whether IL-9 signaling affects central nervous system (CNS)-resident cells during CNS autoimmunity remains unknown. In the present study, we found that the IL-9 receptor (IL-9R) was highly expressed in astrocytes, oligodendrocyte progenitor cells (OPCs), oligodendrocytes and microglia cells, and that its expression was significantly upregulated in brain and spinal cord during EAE. In addition, IL-9 increased chemokine expression, including CXCL9, CCL20 and MMP3, in primary astrocytes. Although IL-9 had no effect on the proliferation of microglia cells, it decreased OPC proliferation and differentiation when in combination with other pro-inflammatory cytokines, but not with IFN-γ. IL-9 plus IFN-γ promoted OPC proliferation and differentiation. These findings indicate that CNS-restricted IL-9 signaling may be involved in the pathogenesis of MS/EAE, thus providing a potential therapeutic target for future MS/EAE treatment through disruption of CNS cell-specific IL-9 signaling.

[Correlation analysis between foliar endophytic fungi of Salvia miltiorrhiza and effective components].

The aim of this study was to comprehensively investigate the correlations between foliar fungal endophyte communities and effective components accumulations in Salvia miltiorrhiza. Foliar samples of S. miltiorrhiza were collected in 5 different areas. Their fungal endophyte communities and effective component contents were determined by denaturing gradient gel electrophoresis (DGGE) and high performance liquid chromatography (HPLC), respectively. The results showed that, for characteristics of foliar fungal endophyte communities and effective component contents, there were both similarities and differences among the five samples. Correlation analysis of DGGEs' band and 24 effective components revealed a significant correlations (P < 0.01). For examples, 4 bands (15, 18, 23 and 26) were all significantly correlated with the accumulations of caffeic acid, salvianolic acid B, salvianolic acid C and dihydrotanshinone I.

Ryanodine receptor 2 contributes to hemorrhagic shock-induced bi-phasic vascular reactivity in rats.

AIM: Ryanodine receptor 2 (RyR2) is a critical component of intracellular Ca(2+) signaling in vascular smooth muscle cells (VSMCs). The aim of this study was to investigate the role of RyR2 in abnormal vascular reactivity after hemorrhagic shock in rats. METHODS: SD rats were hemorrhaged and maintained mean arterial pressure (MAP) at 40 mmHg for 30 min or 2 h, and then superior mesenteric arteries (SMA) rings were prepared to measure the vascular reactivity. In other experiments, SMA rings of normal rats and rat VSMCs were exposed to a hypoxic medium for 10 min or 3 h. SMA rings of normal rats and VSMCs were transfected with siRNA against RyR2. Intracellular Ca(2+) release in VSMCs was assessed using Fura-2/AM. RESULTS: The vascular reactivity of the SMA rings from hemorrhagic rats was significantly increased in the early stage (30 min), but decreased in the late stage (2 h) of hemorrhagic shock. Similar results were observed in the SMA rings exposed to hypoxia for 10 min or 3 h. The enhanced vascular reactivity of the SMA rings exposed to hypoxia for 10 min was partly attenuated by transfection with RyR2 siRNA, whereas the blunted vascular reactivity of the SMA rings exposed to hypoxia for 3 h was partly restored by transfection with RyR2 siRNA. Treatment with the RyR agonist caffeine (1 mmol/L) significantly increased Ca(2+) release in VSMCs exposed to hypoxia for 10 min or 3 h, which was partially antagonized by transfection with RyR2 siRNA. CONCLUSION: RyR2-mediated Ca(2+) release contributes to the development of bi-phasic vascular reactivity induced by hemorrhagic shock or hypoxia.

Daphnetin protects neurons in an Alzheimer disease mouse model and normal rat neurons by inhibiting BACE1 activity and activating the Nrf2/HO-1 pathway.

The common neurodegenerative disorder Alzheimer disease (AD) is characterized by memory dysfunction and cognitive decline in the elderly. Neuropathological features include aggregated ß-amyloid (Aß) accumulation, neuroinflammation, and oxidative stress in the brain. Daphnetin (DAPH), a natural coumarin derivative, has the potential for inhibiting inflammatory and oxidative responses. We explored neuroprotective roles of DAPH treatment in the APP/PS1 transgenic mouse AD model. DAPH ameliorated spatial learning disabilities in Morris water maze tests and reduced Aß deposition, assessed by immunohistochemistry. It also reduced the Aß content in supernatants of neurons from fetal APP/PS1 mice, assessed by cell-based soluble ELISA. Molecular docking and fluorescence resonance energy transfer-based assay results suggested that DAPH could directly inhibit BACE1 activity. Furthermore, in vitro experiments utilizing isolated rat neurons assessing RNA expression profiling, immunofluorescence, TUNEL assay, and Western-blot analysis, suggested the potential of DAPH for regulating BDNF and GM-CSF expression and mitigating Aß1-42-induced cortical injury, synaptic loss, and apoptosis. HO-1 and Nrf2 mRNA and protein expression were also increased in a dose-dependent manner. These results underscore the potential of DAPH as a neuroprotective agent in reversing memory deficits associated with AD and bolster its candidacy as a multitarget natural small-molecule drug for AD patients.

Isoliquiritigenin alleviates experimental autoimmune encephalomyelitis by modulating inflammatory and neuroprotective reactive astrocytes.

Multiple sclerosis (MS) is an autoimmune-mediated chronic inflammatory demyelinating disease of the central nervous system (CNS) that poses significant treatment challenges. Currently, it is believed that inflammatory and neuroprotective reactive astrocytes, along with other resident CNS cells and immune cells, contribute to the pathophysiology of MS. In our study, we found that isoliquiritigenin (ILG), a bioactive chalcone compound, significantly reduces the clinical scores of experimental autoimmune encephalomyelitis (EAE) by 44 % (P < 0.05). Additionally, ILG significantly decreases the pathological scores of spinal cord inflammation and demyelination by 61 % and 65 %, respectively (both P < 0.0001). Furthermore, ILG affects the populations of CD4, Th1, Th17, and Treg cells in vivo. More importantly, ILG significantly promotes the activation of astrocytes in EAE (P < 0.0001). Additionally, ILG treatment indirectly inhibits inflammatory reactive astrocytes and promotes neuroprotective reactive astrocytes. It reduces spleen levels of TNFα, IL1α, C1qa, IL1ß, and IL17A by 95 % (P < 0.001), 98 % (P < 0.01), 46 % (P < 0.05), 97 % (P < 0.001), and 60 % (P < 0.001), respectively. It also decreases CNS levels of TNFα, IL1α, C1qa, IL1ß, and IL17A by 53 % (P < 0.05), 88 % (P < 0.05), 64 % (P < 0.01), 57 % (P < 0.05), and 60 % (P < 0.001), respectively. These results indicate that ILG exerts an immunoregulatory effect by inhibiting the secretion of pro-inflammatory cytokines. Consequently, ILG inhibits inflammatory reactive astrocytes, promotes neuroprotective reactive astrocytes, alleviates inflammation and improves EAE. These findings provide a theoretical basis and support for the application of ILG in the prevention and treatment of MS.

A case report of breast cancer metastasis to the bladder from invasive ductal carcinoma.

Introduction and importance: Breast cancer is the most common malignancy among women worldwide, predominantly manifesting as invasive ductal carcinoma (IDC), which usually metastasizes to the bones, lungs, and liver. However, metastasis to the bladder is exceedingly rare, with few documented cases and limited understanding in the existing literature. Case presentation: A 57-year-old woman with a history of IDC presented with a lump in her left breast and was initially treated with chemotherapy and a modified radical mastectomy. Years later, she developed urinary symptoms, which upon investigation revealed multiple bladder tumors and right kidney hydronephrosis. Diagnostic imaging, including ultrasound and computed tomography (CT) scans, supported these findings. Clinical discussion: The discovery of bladder metastasis from IDC highlights significant diagnostic challenges due to the atypical presentation. The case underscores the importance of considering unusual metastatic sites in patients with known breast cancer, especially when they present with non-specific urinary symptoms. This report explores the potential pathophysiological mechanisms of such rare metastatic occurrences and discusses the implications for clinical practice. Conclusion: This case exemplifies the critical need for heightened awareness and thorough evaluation in patients with unusual symptoms and a history of breast cancer. It calls for more comprehensive diagnostic approaches and possibly adjusted treatment protocols to better manage atypical metastases, ultimately aiming to improve patient outcomes and contribute to a deeper understanding of metastatic breast cancer behavior.

δ opioid receptor antagonist, ICI 174,864, is suitable for the early treatment of uncontrolled hemorrhagic shock in rats.

BACKGROUND: Fluid resuscitation is the essential step for early treatment of traumatic hemorrhagic shock. However, its implementation is greatly limited before hospital or during evacuation. The authors investigated whether δ opioid receptor antagonist ICI 174,864 was suitable for the early treatment of traumatic hemorrhagic shock. METHODS: With uncontrolled hemorrhagic-shock rats, the antishock effects of six dosages of ICI 174,864 (0.1, 0.3, 0.5, 1, 3, and 5 mg/kg) infused with or without a small volume of lactated Ringer's solution (LR) before bleeding controlled or bleeding cessation at different times were observed. RESULTS: ICI 174,864 (0.1-3 mg/kg) with or without 1/4 volume of LR infusion showed dose-dependent increase in the mean arterial blood pressure, and significantly prolonged the survival time and 8-h survival rate, as compared with ICI 174,864 plus 1/2 volume of LR infusion. The best effect was shown with 3 mg/kg of ICI 174,864. Bleeding cessation at 1, 2, or 3 h during infusion of ICI 174,864 (3 mg/kg) plus 1/4 volume of LR improved subsequent treatment (70% 24-h survival rate vs. 50 and 10% 24-h survival rate in hypotensive resuscitation and LR group, respectively). There was significant improvement in hemodynamic parameters, oxygen delivery, and tissue perfusion of hemorrhagic-shock rats with 3 mg/kg of ICI 174,864 plus 1/4 volume of LR infusion. CONCLUSION: δ Opioid receptor antagonist ICI 174,864 alone or with small volume of fluid infusion has good beneficial effect on uncontrolled hemorrhagic shock. Its early application can "buy" time for subsequent treatment of traumatic shock.

Role of adenosine A2A receptor in organ-specific vascular reactivity following hemorrhagic shock in rats.

BACKGROUND: Previous studies have demonstrated differences among organs in terms of shock-induced vascular reactivity and a role for adenosine A2A receptors (A2ARs) in protection against ischemia/reperfusion injury. However, the contributions of A2ARs to organ-specific vascular reactivity and the protection of vascular responsiveness following shock are currently unknown. METHODS: We investigated the role of A2ARs in different arteries, including the left femoral artery (LFA), thoracic aorta (TA), superior mesenteric artery (SMA), right renal artery (RRA), pulmonary artery (PA), and middle cerebral artery (MCA), in hemorrhagic-shock rats. RESULTS: The vascular reactivities of the LFA, SMA, RRA, and MCA increased slightly during early shock and then gradually decreased, whereas those of the PA and TA decreased from the start of shock. Different blood vessels lost vascular reactivity at different rates compared with controls; the LFA had the highest rate of loss (64.51%), followed by the SMA (44.69%), TA (36.06%), PA (37.83%), and RRA (32.33%), whereas the MCA had the lowest rate (18.45%). The rate of loss of vascular reactivity in the different vessels was negatively correlated with A2AR expression levels in normal and shock conditions. The highly selective A2AR agonist CGS 21680 significantly improved vascular reactivity, hemodynamic parameters, and animal survival, whereas the specific antagonist SCH58261 further decreased the shock-induced reduction in vascular reactivity and hemodynamic parameters. CONCLUSIONS: A2ARs are involved in the regulation and protection of vascular reactivity following shock. A2AR activation may have a beneficial effect on hemorrhagic shock by improving vascular reactivity and hemodynamic parameters.

CNS-specific therapy for ongoing EAE by silencing IL-17 pathway in astrocytes.

The interleukin-17 (IL-17) cytokine family is crucial to the progression of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). It has been shown in a neuroectoderm-specific knockout study that astrocyte-restricted ablation of Act1, a key and common transcription factor for signals mediated by IL-17 family members (IL-17A, IL-17F, and IL-17C), ameliorates EAE. However, the effect of Act1 deficiency in astrocytes on ongoing disease, which is of clinical relevance for MS therapy, has not been investigated. Here we report that intracerebroventricular (i.c.v.) injection of a novel lentiviral vector (shAct1) to knockdown Act1 expression in astrocytes effectively inhibited disease progression at EAE induction, clinical onset, and peak of disease (ongoing phases), with significantly reduced numbers of infiltrating inflammatory cells and percentage of Th17 cells in the central nervous system (CNS). This was mainly due to the suppressed expression of Th17-related chemokines in astrocytes, while neurotrophic factors in the CNS and immune responses in the periphery were not affected. These results demonstrate that blocking the IL-17 pathways in astrocytes is a promising therapeutic approach for MS in a CNS-specific manner, which does not interfere with systemic immune responses, a major concern in conventional MS therapy.

Vitamin D, vitamin D supplementation and atrial fibrillation risk in the general population: updated systematic review and meta-analysis of prospective studies.

Background: Since the association of vitamin D with atrial fibrillation (AF) risk is still unclear, we conducted this updated meta-analysis of prospective studies to identify the relationship between vitamin D or vitamin D supplementation and AF in the general population. Methods: We conducted a comprehensive search of multiple databases up to May 2023 for studies reporting vitamin D and AF. The hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled by a random-effects model. Results: A total of seven studies were included in this meta-analysis. Vitamin D deficiency (<20 ng/ml) was associated with increased AF incidence (HR: 1.12, 95% CI: 1.005-1.25). The HR was not significant with vitamin D insufficiency (20-30 ng/ml; HR: 1.09, 95% CI: 0.98-1.21). Each 10 ng/ml increase in serum vitamin D was associated with a significantly decreased AF incidence (HR: 0.95, 95% CI: 0.93-0.97). Two studies reported the effect of vitamin D supplements on AF incidence but reached inconsistent results. Conclusions: Vitamin D deficiency or insufficiency was associated with an increased risk of AF in the general population. The role of vitamin D supplementation in AF prevention needs further investigation.

The association between dietary intake of flavonoids and its subclasses and the risk of metabolic syndrome.

Background: The healthiest way to prevent metabolic syndrome (MetS) is through behavioral and nutritional adjustments. We examined the relationship between total flavonoids intake, flavonoid subclasses, and clinically manifest MetS. Methods: A cross-sectional analysis was conducted among 28,719 individuals from the National Health and Nutrition Examination Survey (NHANES) and Food and Nutrient Database for Dietary Studies (FNDDS) 2007-2011 and 2017-2018. Two 24-h reviews were conducted to determine flavonoids intake and subclasses. The link between flavonoids intake and MetS was investigated using a multivariate logistic regression model. Results: Q2 and Q3 of total flavonoids intake were associated with 20 and 19% lower risk of incident MetS after adjusting age and sex. Anthocyanidins and flavanones intake in Q2 and Q3 substantially reduced the MetS risk compared to Q1. MetS risk decreased steadily as the total intake of flavonoids increased to 237.67 mg/d. Flavanones and anthocyanidins also displayed V-shaped relationship curves (34.37 and 23.13 mg/d). Conclusion: MetS was adversely linked with total flavonoids intake, flavanones, and anthocyanidins. Moreover, the most effective doses of total flavonoids, flavanones, and anthocyanidins were 237.67, 34.37, and 23.13 mg/d, respectively, potentially preventing MetS.