MicroRNA-542-3p targets Pten to inhibit the myoblasts proliferation but suppresses myogenic differentiation independent of targeted Pten.

BACKGROUND: Non-coding RNA is a key epigenetic regulation factor during skeletal muscle development and postnatal growth, and miR-542-3p was reported to be conserved and highly expressed in the skeletal muscle among different species. However, its exact functions in the proliferation of muscle stem cells and myogenesis remain to be determined. METHODS: Transfection of proliferative and differentiated C2C12 cells used miR-542-3p mimic and inhibitor. RT-qPCR, EdU staining, immunofluorescence staining, cell counting kit 8 (CCK-8), and Western blot were used to evaluate the proliferation and myogenic differentiation caused by miR-542-3p. The dual luciferase reporter analysis and rescued experiment of the target gene were used to reveal the molecular mechanism. RESULTS: The data shows overexpression of miR-542-3p downregulation of mRNA and protein levels of proliferation marker genes, reduction of EdU+ cells, and cellular vitality. Additionally, knocking it down promoted the aforementioned phenotypes. For differentiation, the miR-542-3p gain-of-function reduced both mRNA and protein levels of myogenic genes, including MYOG, MYOD1, et al. Furthermore, immunofluorescence staining immunized by MYHC antibody showed that the myotube number, fluorescence intensity, differentiation index, and myotube fusion index all decreased in the miR-542-3p mimic group, compared with the control group. Conversely, these phenotypes exhibited an increased trend in the miR-542-3p inhibitor group. Mechanistically, phosphatase and tensin homolog (Pten) was identified as the bona fide target gene of miR-542-3p by dual luciferase reporter gene assay, si-Pten combined with miR-542-3p inhibitor treatments totally rescued the promotion of proliferation by loss-function of miR-542-3p. CONCLUSIONS: This study indicates that miR-542-3p inhibits the proliferation and differentiation of myoblast and Pten is a dependent target gene of miR-542-3p in myoblast proliferation, but not in differentiation.

A fast-acting lipid checkpoint in G1 prevents mitotic defects.

Lipid synthesis increases during the cell cycle to ensure sufficient membrane mass, but how insufficient synthesis restricts cell-cycle entry is not understood. Here, we identify a lipid checkpoint in G1 phase of the mammalian cell cycle by using live single-cell imaging, lipidome, and transcriptome analysis of a non-transformed cell. We show that synthesis of fatty acids in G1 not only increases lipid mass but extensively shifts the lipid composition to unsaturated phospholipids and neutral lipids. Strikingly, acute lowering of lipid synthesis rapidly activates the PERK/ATF4 endoplasmic reticulum (ER) stress pathway that blocks cell-cycle entry by increasing p21 levels, decreasing Cyclin D levels, and suppressing Retinoblastoma protein phosphorylation. Together, our study identifies a rapid anticipatory ER lipid checkpoint in G1 that prevents cells from starting the cell cycle as long as lipid synthesis is low, thereby preventing mitotic defects, which are triggered by low lipid synthesis much later in mitosis.

Metformin: A promising clinical therapeutical approach for BPH treatment via inhibiting dysregulated steroid hormones-induced prostatic epithelial cells proliferation.

The occurrence of benign prostate hyperplasia (BPH) was related to disrupted sex steroid hormones, and metformin (Met) had a clinical response to sex steroid hormone-related gynaecological disease. However, whether Met exerts an antiproliferative effect on BPH via sex steroid hormones remains unclear. Here, our clinical study showed that along with prostatic epithelial cell (PEC) proliferation, sex steroid hormones were dysregulated in the serum and prostate of BPH patients. As the major contributor to dysregulated sex steroid hormones, elevated dihydrotestosterone (DHT) had a significant positive relationship with the clinical characteristics of BPH patients. Activation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) by Met restored dysregulated sex steroid hormone homeostasis and exerted antiproliferative effects against DHT-induced proliferation by inhibiting the formation of androgen receptor (AR)-mediated Yes-associated protein (YAP1)-TEA domain transcription factor (TEAD4) heterodimers. Met's anti-proliferative effects were blocked by AMPK inhibitor or YAP1 overexpression in DHT-cultured BPH-1 cells. Our findings indicated that Met would be a promising clinical therapeutic approach for BPH by inhibiting dysregulated steroid hormone-induced PEC proliferation.

Gastric acid-responsive deformable sodium alginate/Bletilla striata polysaccharide in situ gel for the protection and treatment of alcohol-induced peptic ulcers.

First-line drugs for peptic ulcer (PU) treatment are typically limited by poor targeting and adverse effects associated with long-term use. Despite recent advancements in novel therapeutic approaches for PU, the development of sustained-release delivery systems tailored to specific pathological characteristics remains challenging. Persistent inflammation, particularly gastric inflammatory microenvironment imbalance, characterizes the PU. In this study, we prepared an in situ gel composed of sodium alginate, deacetylated gellan gum, calcium citrate, and Bletilla striata polysaccharide (BSP) to achieve sustained release of BSP. The BSP in situ gel demonstrated favorable fluidity in vitro and completed self-assembly in vivo in response to the acidic milieu at a pH of 1.5. Furthermore, the shear, extrusion, and deformation properties increased by 26.4 %, 103.7 %, and 46.3 %, respectively, with long-term gastric retention (4 h) and mucosal adaptation. Animal experiments confirmed that the BSP in situ gel could attenuate necrotic injury and inflammatory cell infiltration, maintain mucosal barrier integrity, regulate cytokine imbalance and inflammation-associated hyperapoptosis, thus effectively alleviate the inflammatory microenvironmental imbalance in PU without significant side effects. Overall, our findings demonstrated that the BSP in situ gel is a promising therapeutic strategy for PU and opens avenues for developing self-assembled formulations targeting the pathological features of PUs.

Differential metabolites screening in yak (Bos grunniens) seminal plasma after cryopreservation and the evaluation of the effect of galactose on post-thaw sperm motility.

Sperm survival and activity depend on the provision of energy and nutrients from seminal plasma (SP). This study aimed to investigate the variations of metabolites within SP before and after freezing and subsequently explore the potential regulatory mechanisms affecting yak sperm cryodamage due to changes in metabolites in the SP. Untargeted metabolomics analysis was performed to screen for differential metabolites, followed by KEGG analysis to identify enriched signaling pathways. The combinatorial analysis of metabolomics and sperm proteomics revealed the influence of key SP metabolites on sperm proteins. Subsequently, the relevant differentially expressed proteins were verified by Western blot analysis. Finally, the mechanism underlying the positive effect of galactose on sperm motility was determined by assessing the change in ATP content in sperm before and after freezing and thawing. The data showed that a total of 425 and 269 metabolites were identified in the positive and negative ion modes, respectively. Freezing and thawing resulted in the up-regulation of 70 metabolites and the down-regulation of 29 metabolites in SP. The primary impact of freezing and thawing was observed in carbohydrate metabolism, including pyruvate metabolism, pentose phosphate pathway, galactose metabolism, the TCA cycle, and butanoate metabolism. In the combined analysis and Western blot results, a significant positive correlation was observed between galactose and Aldo-keto reductase family 1 member B1 (AKR1B1) (P < 0.05), which has the ability to convert galactose into galactol. Furthermore, the addition of galactose to thawed semen improved sperm motility by increasing AKR1B1 protein in sperm and was associated with the content of ATP. These data identify differential metabolites between fresh and frozen-thawed SP and suggest that galactose is a valuable additive for cryopreserved sperm, providing a theoretical basis for further exploration of the refrigerant formula for yak sperm cryopreservation.

Atractylodes Processing Products Protect against Gastric Ulcers in Rats by Influencing the NF-κB-MMP-9/TIMP-1 Regulatory Mechanism and Intestinal Flora.

Atractylodes macrocephala Koidz. (AM) is a Chinese herbal medicine that is widely used for treating gastrointestinal diseases. However, little research has focused on it as a single medicine for treating gastric ulcers. Honey-bran stir-frying is a characteristic method of concocting AM, so we speculated that AM is more effective after this preparation process. Analysis by ultra-high-performance liquid chromatography-hybrid quadrupole-Orbitrap high-resolution mass spectrometry revealed changes in the chemical composition of raw Atractylodes (SG), bran-fried Atractylodes (FG), and honey-bran-fried Atractylodes (MFG). MFG was superior to SG and FG in improving the pathological structure of gastric tissue in rats with acute gastric ulcers, reducing inflammatory cell infiltration in gastric tissue, and significantly reducing malondialdehyde while increasing superoxide dismutase and glutathione peroxidase, and reducing the damage caused by free radical accumulation in the gastric mucosa. In addition, MFG reduced the expression of matrix metalloproteinase-9 (MMP-9), an inhibitor of metalloproteinase-1 (TIMP-1) and nuclear factor kappa-B (NF-κB)proteins, inhibited inflammatory response, and regulated the degradation and rebalancing of the extracellular matrix. Fecal microbiota analysis also revealed that MFG normalized the intestinal flora to some extent. Our study shows that AM had a protective effect on rats with alcohol-induced acute gastric ulcers before and after processing, and AM-processed products were more effective than raw ones. Compared with MF, MFG had a higher rate of ulcer inhibition and a stronger anti-inflammatory effect, and its mechanism of action was related to the NF-κB-MMP-9/TIMP-1 signaling pathway.

TMT-based quantitative proteomics analysis reveals the differential proteins between fresh and frozen-thawed sperm of yak (Bos grunniens).

Sperm cryopreservation is one of the most effective methods for the conservation of germplasm resources and used of superior sires widely. However, the motility of yak (Bos grunniens) sperm was low after thawing and the proteomics changes in sperm cryopreservation remain unknown. Therefore, the aim of this study was to explore the differences between fresh sperm and frozen sperm of yak through the proteomic analysis and thus improve the understanding of sperm cryodamage. The Tandem Mass Tags (TMT) technology was used to screen differentially expressed proteins (DEPs) before and after freezing. Then, GO and KEGG analysis were conducted to analyze the DEPs enriched signaling pathways. Finally, the DEPs, including superoxide dismutase 1 (SOD1) and NADH ubiquinone oxidoreductase core subunit S8 (NDUFS8) were verified by the immunofluorescence technique. The results showed that there were 229 DEPs between fresh and frozen-thawed yak sperm. Compared with the fresh sperm, 120 proteins were up-regulated and 109 proteins were down-regulated in frozen-thawed sperm. The GO annotation showed that the up-regulated proteins enriched in metabolic and cytoskeleton-related processes, including lipoprotein metabolic process, lipid transport, extracellular region and intermediate filament cytoskeleton organization. In contrast, the down-regulated proteins enriched in biological processes including single fertilization, sperm capacitation and response to unfolded protein. KEGG pathway analysis indicated that freezing and thawing affected the oxidative phosphorylation pathway, the fructose and mannose metabolic pathway and the glycerolipid metabolic pathway of yak sperm. Immunofluorescence results showed that the protein expression level of SOD1 protein in the frozen group was significantly lower than that in the fresh group (P < 0.01), and the protein expression level of NDUFS8 protein was significantly higher in frozen group (P < 0.01). This study revealed the DEPs between fresh and frozen-thawed sperm and provides a theoretical basis to further explore the exertion of normal biological functions of yak sperm after freezing and thawing.

Interactions between ultrasonographic cervical length and placenta accreta spectrum on severe postpartum hemorrhage in women with placenta previa.

OBJECTIVE: To explore the interactions between cervical length (CL) and placenta accreta spectrum (PAS) on severe postpartum hemorrhage (SPPH) in patients with placenta previa. METHODS: A retrospective case-control study was conducted at four medical centers in China, and 588 patients with placenta previa were included. The logistic regression analysis and restricted cubic splines (RCS) were used to evaluate the association between CL and SPPH. Furthermore, the joint effect of CL and PAS on SPPH was assessed, and the additive and multiplicative interactions were calculated. RESULTS: After adjusting for potential confounders, the negative linear dose-response relationship was confirmed by RCS, and the change of odds ratio (OR) was more significant when CL was 2.5 cm or less. The risk of SPPH was significantly higher when CL of 2.5 cm or less co-existed with placenta increta/percreta than when CL of 2.5 cm less, or placenta increta/percreta existed alone (adjusted OR [aOR]CL ≤2.5cm&placenta accreta/non-PAS 3.40, 95% confidence interval [CI] 1.37-8.45; aORplacenta increta/percreta&CL >2.5cm 4.75, 95% CI 3.03-7.47; aORCL ≤2.5cm&placenta increta/percreta 14.51, 95% CI 6.08-34.64), and there might be additive interaction between CL and placenta increta/percreta on SPPH (attributable proportion due to interaction 50.7%, 95% CI 6.1%-95.3%). CONCLUSION: If CL was routinely performed during PAS evaluation, the increased OR of short CL and PAS could allow better patient preparation through counseling.

In-situ Electrochemical Transformed Cu Oxide from Cu Sulfide for Efficient Upgrading of Biomass Derived 5-Hydroxymethylfurfural in Anion Exchange Membrane Electrolyzer.

The electrochemical transformation of biomass to high value-added products is attractive. Herein, Cu sulfide-mediated in-situ synthesis of Cu oxide was achieved for efficient electro-oxidation of biomass derived 5-hydroxymethylfurfural (HMF) to 2,5-furandicarboxylic acid (FDCA). The copper foam-supported Cu sulfide (Cu-S/CF) was in-situ converted to Cu oxide during the electro-oxidation process. The in-situ formed Cu oxide presented high HMF conversion, FDCA yield, and faradaic efficiency in 1 m KOH with HMF concentration up to 100 mm. The oxidation of HMF on Cu oxide started with the formation of high-valence Cu species with the assistance of OH- , which then oxidized HMF spontaneously. An anion exchange membrane (AEM) electrolyzer with Cu-S/CF as the anode was assembled to continuously produce FDCA with H2 generation at the cathode. The AEM electrolyzer ran stably for 60 h with FDCA content higher than 85 % at a cell voltage between 1.50 and 1.60 V.

Distributed Acoustic Sensing (DAS) Response of Rising Taylor Bubbles in Slug Flow.

Slug flow is one of the most common flow types encountered in surface facilities, pipelines, and wellbores. The intermittent gas phase, in the form of a Taylor bubble, followed by the liquid phase can be destructive to equipment. However, commonly used point flow sensors have significant limitations for flow analysis. Distributed acoustic sensing (DAS) can turn optical fibers into an array of distributed strain rate sensors and provide substantial insights into flow characterization. We built a 10 m vertical laboratory flow loop equipped with wrapped fiber optic cables to study the DAS response of rising Taylor bubbles. Low-passed DAS data allow for velocity tracking of Taylor bubbles of different sizes and water velocities. Moreover, we measured the velocity of the wake region following the Taylor bubble and explored the process of Taylor bubbles merging. The amplitude analysis of DAS data allows for the estimation of Taylor bubble size. We conclude that DAS is a promising tool for understanding Taylor bubble properties in a laboratory environment and monitoring destructive flow in facilities across different industries to ensure operations are safe and cost-effective.

Vitamin D supplementation for the treatment of migraine: A meta-analysis of randomized controlled studies.

INTRODUCTION: It is not well established to use vitamin D supplementation for migraine, and this meta-analysis aims to explore the efficacy of vitamin D for migraine patients. METHODS: PubMed, EMbase, Web of science, EBSCO and Cochrane library databases were systematically searched up to May 2021, and we included randomized controlled trials (RCTs) exploring the effect of vitamin D for migraine patients. RESULTS: Six RCTs and 301 patients were included in the meta-analysis. Compared with control group in migraine patients, vitamin D supplementation could remarkably decrease headache attacks per month (MD = -2.74; 95% CI = -3.82 to -1.67; P < 0.00001), headache days per month (MD = -1.56; 95% CI = -2.44 to -0.68; P = 0.0005) and MIDAS score (MD = -5.72; 95% CI = -10.90 to -0.54; P = 0.03), but demonstrated no obvious influence on attack duration (MD = -2.20; 95% CI = -7.38 to 2.97; P = 0.40) or headache severity (MD = -0.56; 95% CI = -1.18 to 0.06; P = 0.08). CONCLUSIONS: Vitamin D supplementation provided additional benefits to treat migraine.

Molecular control of cell density-mediated exit to quiescence.

Contact inhibition of cell proliferation regulates tissue size and prevents uncontrolled cell expansion. When cell density increases, contact inhibition can force proliferating cells into quiescence. Here we show that the variable memory of local cell density experienced by a mother cell controls the levels of the cyclin-dependent kinase (CDK) activator cyclin D1 and inhibitor p27 in newborn daughters, which direct cells to proliferation or quiescence. Much of this regulation can be explained by rapid suppression of ERK activity by high cell density in mothers, which leads to lower cyclin D1 and higher p27 levels in daughters. Strikingly, cell density and mitogen signals compete by shifting the ratio of cyclin D1/p27 levels below or above a single sharp threshold that controls the proliferation decision. Thus, the history of competing cell density and mitogen signals experienced by mothers is funneled into a precise activator-inhibitor balance that decides the fate of daughter cells.

LRR1-mediated replisome disassembly promotes DNA replication by recycling replisome components.

After two converging DNA replication forks meet, active replisomes are disassembled and unloaded from chromatin. A key process in replisome disassembly is the unloading of CMG helicases (CDC45-MCM-GINS), which is initiated in Caenorhabditis elegans and Xenopus laevis by the E3 ubiquitin ligase CRL2LRR1. Here, we show that human cells lacking LRR1 fail to unload CMG helicases and accumulate increasing amounts of chromatin-bound replisome components as cells progress through S phase. Markedly, we demonstrate that the failure to disassemble replisomes reduces the rate of DNA replication increasingly throughout S phase by sequestering rate-limiting replisome components on chromatin and blocking their recycling. Continued binding of CMG helicases to chromatin during G2 phase blocks mitosis by activating an ATR-mediated G2/M checkpoint. Finally, we provide evidence that LRR1 is an essential gene for human cell division, suggesting that CRL2LRR1 enzyme activity is required for the proliferation of cancer cells and is thus a potential target for cancer therapy.

H2S promotes developmental brain angiogenesis via the NOS/NO pathway in zebrafish.

BACKGROUND: Hydrogen sulphide (H2S) is considered as the third member of the gasotransmitter family, along with nitric oxide (NO) and carbon monoxide. H2S has been reported to induce angiogenesis by promoting the growth, migration and tube-like structure formation of endothelial cells. Those studies were conducted in conditions of cell culture, mouse Matrigel plug assay model, rat wound healing model or rat hindlimb ischaemia model. Recent in vivo studies showed the physiological importance of H2S in muscle angiogenesis. However, the importance of endogenous H2S for brain angiogenesis during development remains unknown. We therefore aimed at determining the role of H2S in brain vascular development. METHODS AND RESULTS: Both knockdown and knockout of H2S-producing enzymes, cystathionine ß-synthase (cbs) and cystathionine γ-lyase (cth), using morpholino oligonucleotides and clustered regularly interspaced short palindromic repeats/Cas9-mediated mutation, impaired brain vascular development of larval zebrafish. Incubation with the slow-releasing H2S donor GYY4137 alleviated the defects of brain vascular development in cbs and cth morphants. Quantitative analysis of the midbrain vascular network showed that H2S enhances angiogenesis without affecting the topological structure of the brain vasculature. Mechanically, nitric oxide synthase 2a (nos2a) expression and NO production were decreased in both cbs and cth morphants. Overexpression of nos2a by coinjection of cbs or cth MO with full-length zebrafish nos2a mRNA alleviated the brain vascular developmental defects in cbs and cth morphants. CONCLUSION: We conclude that H2S promotes brain developmental angiogenesis via the NOS/NO pathway in zebrafish.

Mitochondrial genome of Chalcidoidea sp. (Hymenoptera: Apocrita: Chalcidoidea) and phylogenetic analysis.

Chalcidoidea (Hymenoptera) are minute wasps which can attack immature and adult stages of virtually all insect orders. Here, we sequenced and annotated the mitochondrial genome (mitogenome) of Chalcidoidea sp. This mitogenome was 15,152 bp long and encoded 13 protein-coding genes (PCGs), 20 transfer RNA genes (tRNAs), and 2 ribosomal RNA unit genes (rRNAs). All 13 PCGs were initiated by the ATN (ATG, ATT, ATA, and ATC) codon. All PCGs terminate with the stop codons TAA or TAG except for nad4 which ended with the incomplete codon T-. Phylogenetic analysis showed that Chalcidoidea sp. got together with the species Encyrtus infelix and Eurytoma sp., and species in Chalcidoidea formed a sister group to other Cynipoidea and Proctotrupoidea species.

Altered G1 signaling order and commitment point in cells proliferating without CDK4/6 activity.

Cell-cycle entry relies on an orderly progression of signaling events. To start, cells first activate the kinase cyclin D-CDK4/6, which leads to eventual inactivation of the retinoblastoma protein Rb. Hours later, cells inactivate APC/CCDH1 and cross the final commitment point. However, many cells with genetically deleted cyclin Ds, which activate and confer specificity to CDK4/6, can compensate and proliferate. Despite its importance in cancer, how this entry mechanism operates remains poorly characterized, and whether cells use this path under normal conditions remains unknown. Here, using single-cell microscopy, we demonstrate that cells with acutely inhibited CDK4/6 enter the cell cycle with a slowed and fluctuating cyclin E-CDK2 activity increase. Surprisingly, with low CDK4/6 activity, the order of APC/CCDH1 and Rb inactivation is reversed in both cell lines and wild-type mice. Finally, we show that as a consequence of this signaling inversion, Rb inactivation replaces APC/CCDH1 inactivation as the point of no return. Together, we elucidate the molecular steps that enable cell-cycle entry without CDK4/6 activity. Our findings not only have implications in cancer resistance, but also reveal temporal plasticity underlying the G1 regulatory circuit.

Effectiveness of neuromuscular electrical stimulation for endometriosis-related pain: A protocol of systematic review and meta-analysis.

BACKGROUND: This study will assess the effectiveness and safety of neuromuscular electrical stimulation (NMES) for endometriosis-related pain (ERP). METHODS: Seven electronic databases of Cochrane Library, PUBMED, EMBASE, WANGFANG, VIP, CBM, and CNKI will be searched. We will search all electronic databases related the randomized controlled trials (RCTs) on the effectiveness and safety of NMES for ERP up to the March 31, 2020 without restrictions of language. RevMan 5.3 software will be used for risk of bias assessment, related data analysis and meta-analysis. RESULTS: This systematic review and meta-analysis will summarize current high-quality RCTs on the effectiveness and safety of NMES for ERP. Results of this study will provide the basis for both clinician and further research. CONCLUSION: This study will investigate whether NMES is effective and safety for the treatment of ERP. SYSTEMATIC REVIEW REGISTRATION: INPLASY202040191.

Stress-mediated exit to quiescence restricted by increasing persistence in CDK4/6 activation.

Mammalian cells typically start the cell-cycle entry program by activating cyclin-dependent protein kinase 4/6 (CDK4/6). CDK4/6 activity is clinically relevant as mutations, deletions, and amplifications that increase CDK4/6 activity contribute to the progression of many cancers. However, when CDK4/6 is activated relative to CDK2 remained incompletely understood. Here, we developed a reporter system to simultaneously monitor CDK4/6 and CDK2 activities in single cells and found that CDK4/6 activity increases rapidly before CDK2 activity gradually increases, and that CDK4/6 activity can be active after mitosis or inactive for variable time periods. Markedly, stress signals in G1 can rapidly inactivate CDK4/6 to return cells to quiescence but with reduced probability as cells approach S phase. Together, our study reveals a regulation of G1 length by temporary inactivation of CDK4/6 activity after mitosis, and a progressively increasing persistence in CDK4/6 activity that restricts cells from returning to quiescence as cells approach S phase.

Bile duct ligation enhances AZT CNS toxicity partly by impairing the expression and function of BCRP in rat brain.

Breast cancer resistance protein (BCRP) is one of ATP-binding cassette (ABC) transporters in brain microvessel endothelial cells that transport their substrates from brain to blood, thus limiting substrates to crossing into brain through blood-brain barrier. Our previous works show that bile duct ligation (BDL) impairs expression and function of brain BCRP in rats. Since zidovudine (AZT) is BCRP substrate, we investigated whether impaired expression and function of BCRP increased brain distribution and toxicity of AZT in BDL-D7 rats. After administration of AZT (10 mg/kg, i.v.), BDL markedly increased brain AZT concentrations, compared with sham-operated (SO) rats. The ratio of AZT brain-to-plasma area under concentration curve (AUC) in BDL rats was increased to 1.6-folds of SO rats. After treatment with AZT (100 mg/kg every day, i.v.) for 7 days, BDL significantly impaired cognitive functions compared with SO rats, evidenced by the significantly decreased percentage of alternation in Y-maze test and prolonged escaped latency in two-way passive avoidance trial. Furthermore, AZT treatment caused significant decrease in copies of mitochondrial DNA and mitochondrial membrane potential in hippocampus of BDL rats. Moreover, AZT treatment caused a significant decrease of cortex microtubule-associated protein 2 and hippocampus synaptophysin levels in BDL rats. AZT-induced CNS adverse alterations in BDL rats were not observed in SO rats treated with AZT. In conclusion, BDL decreases the function and expression of brain BCRP in rats, leading to increased brain distribution of AZT, which in turn enhances AZT CNS toxicity, leading to mitochondrial dysfunction, neuronal damage, and ultimately cognitive dysfunction.

Cardioprotection of (±)-sodium 5-bromo-2-(α-hydroxypentyl) benzoate (BZP) on mouse myocardium I/R injury through inhibiting 12/15-LOX-2 activity.

(±)-Sodium5-bromo-2-(α-hydroxypentyl) benzoate (brand name: brozopine, BZP, 1a), derived from L-3-n-butylphthalide (L-NBP), has been reported to protect the brain from stoke and has been approved by CFDA in Phase I-II clinical trials. However, it remains to be investigated whether 1a may exhibit any cardioprotective effect on ischemia-reperfusion (I/R) injury. In the current study, C57BL/6 and ICR mice were pretreated with 1a, and myocardium I/R were then performed. We found that 1a not only significantly reduced the infarct size and improved cardiac contractile function after acute MI/R in both species, but also protected hearts from chronic MI-related cardiac injury. Mechanically, we found that 1a physically binds to 12/15-LOX-2 using molecular docking. The shRNA-mediated 12/15-LOX-2 knockdown almost completely blocked the protective effect of 1a. Our findings, for the first time, strongly indicate that 1a may serve as a potent and promising cardioprotective agent in treatment of I/R related injury, at least partially through targeting 12/15-LOX-2.