The fate of sulfonamides in microenvironments of rape and hot pepper rhizosphere soil system.

Sulfonamides (SAs) in agricultural soils can be degraded in rhizosphere, but can also be taken up by vegetables, which thereby poses human health and ecological risks. A glasshouse experiment was conducted using multi-interlayer rhizoboxes to investigate the fate of three SAs in rape and hot pepper rhizosphere soil systems to examine the relationship between the accumulation and their physicochemical processes. SAs mainly entered pepper shoots in which the accumulation ranged from 0.40 to 30.64 mg kg-1, while SAs were found at high levels in rape roots ranged from 3.01 to 16.62 mg kg-1. The BCFpepper shoot exhibited a strong positive linear relationship with log Dow, while such relationship was not observed between other bioconcentration factors (BCFs) and log Dow. Other than lipophilicity, the dissociation of SAs may also influence the uptake and translocation process. Larger TF and positive correlation with log Dow indicate preferential translocation of pepper SAs. There was a significant (p < 0.05) dissipation gradient of SAs observed away from the vegetable roots. In addition, pepper could uptake more SAs under solo exposure, while rape accumulated more SAs under combined exposure. When SAs applied in mixture, competition between SAs might occur to influence the translocation and dissipation patterns of SAs.

The phloem and xylem structure of plants and the neutral and ionic partitioning of sulfonamides (SAs) influence the uptake and translocation of SAs.A significant (p < 0.05) dissipation gradient of SAs was observed away from the vegetable roots.Combined exposure could promote the correlation between log BCF and log D_ow.

An integrated analytical strategy to decipher the metabolic profile of alkaloids in Compound Kushen injection based on UHPLC-ESI-QTOF/MSE.

Compound Kushen injection (CKI) is a kind of sterilised water-soluble traditional Chinese medicine preparation that has been used for the clinical treatment of a variety of cancers (hepatocellular carcinoma, lung cancer, etc.) for 19 years. However, to date, the metabolism-related study on CKI in vivo has not been conducted.An integrated analytical strategy was established to investigate the metabolic profile of alkaloids of CKI in rat plasma, urine, and faeces based on ultra-high performance liquid chromatography-electrospray quadrupole time-of-flight mass spectrometry in MSE mode (UHPLC-ESI-QTOF/MSE).Nineteen prototype alkaloids (including 12 matrine-type alkaloids, 2 cytisine-type alkaloids, 3 lupinine-type alkaloids, and 2 aloperine-type alkaloids) of CKI were identified in vivo. Furthermore, 71 metabolites of alkaloids (including 11 of lupanine-related metabolites, 14 of sophoridine-related metabolites, 14 of lamprolobine-related metabolites, and 32 of baptifoline-related metabolites) were tentatively characterised. Metabolic pathways involved in the metabolism of phase I (include oxidation, reduction, hydrolysis, and desaturation), phase II (mainly include glucuronidation, acetylcysteine or cysteine conjugation, methylation, acetylation, and sulphation), and associated combination reactions.The integrated analytical strategy was successfully used to characterise the prototype alkaloids and their metabolites of CKI in vivo, and the results laying a foundation for further study its pharmacodynamic substances.

Effect of dapagliflozin on diabetic patients with cardiovascular disease via MAPK signalling pathway.

Clinical studies have shown that dapagliflozin can reduce cardiovascular outcome in patients with type 2 diabetes mellitus (T2DM), but the exact mechanism is unclear. In this study, we used the molecular docking and network pharmacology methods to explore the potential mechanism of dapagliflozin on T2DM complicated with cardiovascular diseases (CVD). Dapagliflozin's potential targets were predicted via the Swiss Target Prediction platform. The pathogenic targets of T2DM and CVD were screened by the Online Mendelian Inheritance in Man (OMIM) and Gene Cards databases. The common targets of dapagliflozin, T2DM and CVD were used to establish a protein-protein interaction (PPI) network; the potential protein functional modules in the PPI network were found out by MCODE. Metascape tool was used for Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analysis. A potential protein functional module with the best score was obtained from the PPI network and 9 targets in the protein functional module all showed good binding properties when docking with dapagliflozin. The results of KEGG pathway enrichment analysis showed that the underlying mechanism mainly involved AGE-RAGE signalling pathway in diabetic complications, TNF signalling pathway and MAPK signalling pathway. Significantly, the MAPK signalling pathway was considered as the key pathway. In conclusion, we speculated that dapagliflozin played a therapeutic role in T2DM complicated with CVD mainly through MAPK signalling pathway. This study preliminarily reveals the possible mechanism of dapagliflozin in the treatment of T2DM complicated with CVD and provides a theoretical basis for future clinical research.

The variations of endophilin A2-FoxO3a-autophagy signal in angiotensin II-induced dopaminergic neuron injury mouse model and by biochanin A.

Biochanin A (Bioch A) is a natural plant estrogen, with various biological activities such as anti-apoptosis, anti-oxidation, and suppression of inflammation. In this study, we investigated the protective effects of Bioch A on angiotensin II (AngII) - induced dopaminergic (DA) neuron damage in vivo and on molecular mechanisms. Spontaneous activity and motor ability of mice among groups was detected by open-field test and swim-test. The expression of TH, microtubule-associated proteins light chain 3B II (LC3BII)/LC3BI, beclin-1, P62, forkhead box class O3 (FoxO3), phosphorylated (p) FoxO3a/FoxO3a, FoxO3, and endophilin A2 were determined by Western blot and immunohistochemistry or immunofluorescence staining. Our results showed that AngII treatment significantly increased the behavioral dysfunction of mice and DA neuron damage. Meanwhile, AngII treatment increased the expression of LC3BII/LC3BI, beclin-1, P62, and FoxO3a and decreased the expression of endophilin A2 and p-FoxO3a/FoxO3a, however, Bioch A treatment alleviate these changes. In summary, these results suggest that Bioch A exerts protective effects on AngII-induced mouse model may be related to regulating endophilin A2, FoxO3a, and autophagy-related proteins; however, the specific mechanism is not yet clear and needs further study.

Spinal cord NLRP1 inflammasome contributes to dry skin induced chronic itch in mice.

BACKGROUND: Dry skin itch is one of the most common skin diseases and elderly people are believed to be particularly prone to it. The inflammasome has been suggested to play an important role in chronic inflammatory disorders including inflammatory skin diseases such as psoriasis. However, little is known about the role of NLRP1 inflammasome in dry skin-induced chronic itch. METHODS: Dry skin-induced chronic itch model was established by acetone-ether-water (AEW) treatment. Spontaneous scratching behavior was recorded by video monitoring. The expression of nucleotide oligomerization domain (NOD)-like receptor protein 1 (NLRP1) inflammasome complexes, transient receptor potential vanilloid type 1 (TRPV1), and the level of inflammatory cytokines were determined by western blot, quantitative real-time PCR, and enzyme-linked immunosorbent assay (ELISA) kits. Nlrp1a knockdown was performed by an adeno-associated virus (AAV) vector containing Nlrp1a-shRNA-eGFP infusion. H.E. staining was used to evaluate skin lesion. RESULTS: AEW treatment triggers spontaneous scratching and significantly increases the expression of NLRP1, ASC, and caspase-1 and the levels of IL-1ß, IL-18, IL-6, and TNF-α in the spinal cord and the skin of mice. Spinal cord Nlrp1a knockdown prevents AEW-induced NLRP1 inflammasome assembly, TRPV1 channel activation, and spontaneous scratching behavior. Capsazepine, a specific antagonist of TRPV1, can also inhibit AEW-induced inflammatory response and scratching behavior. Furthermore, elderly mice and female mice exhibited more significant AEW-induced scratching behavior than young mice and male mice, respectively. Interestingly, AEW-induced increases in the expression of NLRP1 inflammasome complex and the levels of inflammatory cytokines were more remarkable in elderly mice and female mice than in young mice and male mice, respectively. CONCLUSIONS: Spinal cord NLRP1 inflammasome-mediated inflammatory response contributes to dry skin-induced chronic itch by TRPV1 channel, and it is also involved in age and sex differences of chronic itch. Inhibition of NLRP1 inflammasome may offer a new therapy for dry skin itch.

Biochanin A protects against angiotensin II-induced damage of dopaminergic neurons in rats associated with the increased endophilin A2 expression.

The brain renin-angiotensin system plays a vital role in the modulation of the neuroinflammatory responses and the progression of dopaminergic (DA) degeneration. Angiotensin II (Ang II) induces microglia activation via angiotensin II type 1 receptor (AT1R), which in turn affects the function of DA neurons. Endophilin A2 (EPA2) is involved in fast endophilin-mediated endocytosis and quickly endocytoses several G-protein-coupled receptor (GPCR), while AT1R belongs to GPCR family. Therefore, we speculated that EPA2 may modulate microglia activation via endocytosing AT1R. Biochanin A is an O-methylated isoflavone, classified as a kind of phytoestrogen due to its chemical structure that is similar to mammalian estrogens. In this study, we investigated the protective effects of biochanin A on Ang II-induced DA neurons damage in vivo, and molecular mechanisms. The results showed that biochanin A treatment for 7 days attenuated the behavioral dysfunction, inhibited the microglial activation, and prevented DA neuron damage in Ang II-induced rats. Furthermore, biochanin A increased EPA2 expression and decreased the expression of AT1R, gp91phox, p22 phox, NLRP3, ASC, Caspase-1, IL-1ß, IL-6, IL-18, and TNF-α. In summary, these results suggest that biochanin A exerts protective effects in Ang II-induced model rats, and the mechanisms may involve inhibition of inflammatory responses, an increase in EPA2 expression and a decrease in AT1R expression.

Epidemiology of acute kidney injury in intensive care units in Beijing: the multi-center BAKIT study.

BACKGROUND: Acute kidney injury (AKI) commonly occurs in intensive care units (ICUs), leading to adverse clinical outcomes and increasing costs. However, there are limited epidemiological data of AKI in the critically ill in Beijing, China. METHODS: In this prospective cohort study in 30 ICUs, we screened the patients up to 10 days after ICU admission. Characteristics and outcomes were compared between AKI and non-AKI, renal replacement therapy (RRT) and non-RRT patients. Nomograms of logistic regression and Cox regression were performed to examine potential risk factors for AKI and mortality. RESULTS: A total of 3107 patients were included in the final analysis. The incidence of AKI was 51.0%; stages 1 to 3 accounted for 23.1, 11.8, and 15.7%, respectively. The majority (87.6%) of patients with AKI developed AKI on the first 4 days after admission to the ICU. A total of 281 patients were treated with RRT. Continuous RRT with predilution, citrate for anticoagulation and femoral vein for vascular access was the most common RRT pattern (29.9%, 84 of 281). Patients with AKI were associated with longer ICU-LOS and higher mortality and costs (P<0.001). In patients treated with RRT, 78.6 and 28.5% of RRTs were dependent on the 7th and 28th days, respectively. The 28 day mortalities of non-AKI, AKI stages 1-3, and septic shock patients were 6.83, 15.04, 27.99, 45.18 and 36.5%, respectively. CONCLUSIONS: Approximately half of our ICU patients experienced AKI. The majority of patients with AKI developed AKI during the first 4 days after admission to the ICU. Continuous RRT with predilution, citrate for anticoagulation and femoral vein for vascular access was the most common RRT pattern in our ICUs. AKI was associated with a higher mortality and costs, incomplete kidney recovery and s series of adverse outcomes.

Sinomenine exerts anticonvulsant profile and neuroprotective activity in pentylenetetrazole kindled rats: involvement of inhibition of NLRP1 inflammasome.

BACKGROUND: Epilepsy is a common neurological disorder and is not well controlled by available antiepileptic drugs (AEDs). Inflammation is considered to be a critical factor in the pathophysiology of epilepsy. Sinomenine (SN), a bioactive alkaloid with anti-inflammatory effect, exerts neuroprotective activity in many nervous system diseases. However, little is known about the effect of SN on epilepsy. METHODS: The chronic epilepsy model was established by pentylenetetrazole (PTZ) kindling. Morris water maze (MWM) was used to test spatial learning and memory ability. H.E. staining and Hoechst 33258 staining were used to evaluate hippocampal neuronal damage. The expression of nucleotide oligomerization domain (NOD)-like receptor protein 1 (NLRP1) inflammasome complexes and the level of inflammatory cytokines were determined by western blot, quantitative real-time PCR and enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: SN (20, 40, and 80 mg/kg) dose-dependently disrupts the kindling acquisition process, which decreases the seizure scores and the incidence of fully kindling. SN also increases the latency of seizure and decreases the duration of seizure in fully kindled rats. In addition, different doses of SN block the hippocampal neuronal damage and minimize the impairment of spatial learning and memory in PTZ kindled rats. Finally, PTZ kindling increases the expression of NLRP1 inflammasome complexes and the levels of inflammatory cytokines IL-1ß, IL-18, IL-6, and TNF-α, which are all attenuated by SN in a dose- dependent manner. CONCLUSIONS: SN exerts anticonvulsant and neuroprotective activity in PTZ kindling model of epilepsy. Disrupting the kindling acquisition, which inhibits NLRP1 inflammasome-mediated inflammatory process, might be involved in its effects.

Chronic glucocorticoid exposure activates BK-NLRP1 signal involving in hippocampal neuron damage.

BACKGROUND: Neuroinflammation mediated by NLRP1 (nucleotide-binding oligomerization domain (NOD)-like receptor protein 1) inflammasome plays an important role in many neurological diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). Our previous studies showed that chronic glucocorticoid (GC) exposure increased brain inflammation via NLRP1 inflammasome and induce neurodegeneration. However, little is known about the mechanism of chronic GC exposure on NLRP1 inflammasome activation in hippocampal neurons. METHODS: Hippocampal neurons damage was assessed by LDH kit and Hoechst 33258 staining. The expression of microtubule-associated protein 2 (MAP2), inflammasome complex protein (NLRP1, ASC and caspase-1), inflammatory cytokines (IL-1ß), and large-conductance Ca2+ and voltage-activated K+ channel (BK channels) protein was detected by Western blot. The inflammatory cytokines (IL-1ß and IL-18) were examined by ELISA kit. The mRNA levels of NLRP1, IL-1ß, and BK were detected by real-time PCR. BK channel currents were recorded by whole-cell patch-clamp technology. Measurement of [K+]i was performed by ion-selective electrode (ISE) technology. RESULTS: Chronic dexamethasone (DEX) treatment significantly increased LDH release and neuronal apoptosis and decreased expression of MAP2. The mechanistic studies revealed that chronic DEX exposure significantly increased the expression of NLRP1, ASC, caspase-1, IL-1ß, L-18, and BK protein and NLRP1, IL-1ß and BK mRNA levels in hippocampal neurons. Further studies showed that DEX exposure results in the increase of BK channel currents, with the subsequent K+ efflux and a low concentration of intracellular K+, which involved in activation of NLRP1 inflammasome. Moreover, these effects of chronic DEX exposure could be blocked by specific BK channel inhibitor iberiotoxin (IbTx). CONCLUSION: Our findings suggest that chronic GC exposure may increase neuroinflammation via activation of BK-NLRP1 signal pathway and promote hippocampal neurons damage, which may be involved in the development and progression of AD.

Chronic glucocorticoids exposure enhances neurodegeneration in the frontal cortex and hippocampus via NLRP-1 inflammasome activation in male mice.

Neuroinflammation plays an important role in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD) and depression. Chronic glucocorticoids (GCs) exposure has deleterious effects on the structure and function of neurons and is associated with development and progression of AD. However, little is known about the proinflammatory effects of chronic GCs exposure on neurodegeneration in brain. Therefore, the aim of this study was to evaluate the effects of chronic dexamethasone (DEX) treatment (5mg/kg, s.c. for 7, 14, 21 and 28 days) on behavior, neurodegeneration and neuroinflammatory parameters of nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 1 (NLRP-1) inflammasome in male mice. The results showed that DEX treatment for 21 and 28 days significantly reduced the spontaneous motor activity and exploratory behavior of the mice. In addition, these mice showed significant neurodegeneration and a decrease of microtubule-associated protein 2 (MAP2) in the frontal cortex and hippocampus CA3. DEX treatment for 7, 14, 21 and 28 days significantly decreased the mRNA and protein expression of glucocorticoid receptor (GR). Moreover, DEX treatment for 21 and 28 days significantly increased the proteins expression of NLRP-1, Caspase-1, Caspase-5, apoptosis associated speck-like protein (ASC), nuclear factor-κB (NF-κB), p-NF-κB, interleukin-1ß (IL-1ß), IL-18 and IL-6 in the frontal cortex and hippocampus brain tissue. DEX treatment for 28 days also significantly increased the mRNA expression levels of NLRP-1, Caspase-1, ASC and IL-1ß. These results suggest that chronic GCs exposure may increase brain inflammation via NLRP-1 inflammasome activation and induce neurodegeneration.

Preparation and Gas Sensing Properties of Hollow ZnS Microspheres.

Hollow ZnS microspheres are synthesized by a facile hydrothermal method. Morphology and structure of the ZnS microspheres are analyzed by SEM, TEM, XRD and N2 sorption technique, Gas sensing properties of the as-prepared ZnS sensor are also systematically investigated. The results show that the ZnS microspheres have well-developed porous and hollow nanostructure. The sensor based on the ZnS microspheres exhibits ultra-fast response (1-2 s) and fast recovery time (7-34 s) towards ethanol at the optimal operating temperature of 160 degrees C. Moreover, the ZnS sensor also demonstrates high selectivity to other gases such as methanol, benzene, dichloromethane and hexane, suggesting that it is a promising candidate for ethanol sensing applications.

Synthesis and antitumor activity evaluation of lamiridosin A derivatives.

A series of lamiridosin A derivatives were synthesized through simple procedures. Their antitumor activities were evaluated against EC9706, MGC803, and B16 cell lines in vitro. Several compounds showed potent antitumor activity, especially compound 10, with IC50 value of 2.36 µmol/L against MGC803 cell lines, is more potent than marketed positive drug 5-fluorouridine (5-FU).

[Near Infrared Spectroscopy Wavelength Selection Method and the Application Based on Synergy Interval Gaussian Process].

Based on Gaussian Process (GP), a wavelength selection algorithm named Synergy Interval Gaussian Process (siGP) model is proposed in this paper by using near infrared spectroscopy technology. Full spectrum is divided into a series of unique and equal spacing intervals, before selecting optimal several intervals to establish GP model. Due to the GP model with nonlinear processing ability, the method reduces the disadvantages of nonlinear factor. Taking the near infrared spectrum data of moisture content and pH in solid-state fermentation of monascus as performance verification object of this new algorithm, the prediction correlation coefficient (Rp) of moisture content and pH are 0.956 4 and 0.977 3, respectively. The root mean square errors for prediction set (RMSEP) are 0.012 7 and 0.161 0, respectively. Data points participating in modeling decrease respectively from the original 1 500 to 225 and 375. In the prediction for independent samples, it shows good accuracy. Comparing with traditional synergy interval partial least squares (siPLS) algorithm, the results show that the siGP achieves the best prediction result. The prediction correlation coefficient of moisture content and pH in new algorithm has increased respectively by 3.37% and 3.51% under the model of Gaussian Process, with increases of 29.4% and 34.8% in the root mean square errors for prediction set. This study shows that the combination of siGP and GP model can select wavelength effectively and improves the prediction accuracy of the NIR model. This method is reference for realizing the online detection and optimization control.

Acid-sensing ion channel 1a contributes to the effect of extracellular acidosis on NLRP1 inflammasome activation in cortical neurons.

BACKGROUND: Acid-sensing ion channels (ASICs) are cation channels which were activated by extracellular acidosis and involved in various physiological and pathological processes in the nervous system. Inflammasome is a key component of the innate immune response in host against harmful and irritable stimuli. As the first discovered molecular platform, NLRP1 (nucleotide-binding oligomerization domain (NOD)-like receptor protein 1) inflammasome is expressed in neurons and implicated in many nervous system diseases such as brain injury, nociception and epilepsy. However, little is known about the effect of ASICs on NLRP1 inflammasome activation under acidosis. METHODS: The expression of inflammasome complex protein (NLRP1, ASC (apoptosis-associated speck-like protein containing a caspase-activating recruitment domain) and caspase-1), inflammatory cytokines (IL-1ß and IL-18), and apoptosis-related protein (Bax, Bcl-2, and activated caspase-3) was detected by Western blot. Large-conductance Ca(2+) and voltage-activated K(+) (BK) channel currents were recorded by whole-cell patch-clamp technology. Measurement of [K(+)] i was performed by fluorescent ion imaging system. Co-expression of ASICs and BK channels was determined by dual immunofluorescence. Cell viability was assessed by MTT and LDH kit. RESULTS: ASICs and BK channels were co-expressed in primary cultured cortical neurons. Extracellular acidosis increased the expression of NLRP1, ASC, caspase-1, IL-1ß, and IL-18. Further mechanistic studies revealed that acidosis-induced ASIC1a activation results in the increase of BK channel currents, with the subsequent K(+) efflux and a low concentration of intracellular K(+), which activated NLRP1 inflammasome. Furthermore, these effects of acidosis could be blocked by specific ASIC1a inhibitor PcTX1 and BK channel inhibitor IbTX. The data also demonstrated neutralization of NLRP1-protected cortical neurons against injury induced by extracellular acidosis. CONCLUSIONS: Our data showed that NLRP1 inflammasome could be activated by extracellular acidosis though ASIC-BK channel K(+) signal pathway and was involved in extracellular acidosis-induced cortical neuronal injury.

Negative interplay of retinoic acid and TGF-ß signaling mediated by TG-interacting factor to modulate mouse embryonic palate mesenchymal-cell proliferation.

Mesenchymal-cell proliferation is the main process in shelf outgrowth. Both all-trans-retinoic acid (atRA) and transforming growth factor-ß3 (TGF-ß3) play an important role in mouse embryonic palate mesenchymal (MEPM) cell proliferation. In the present study, we investigated the crosstalk between RA and TGF-ß signaling in MEPM-cell proliferation. We found that atRA inhibited MEPM-cell proliferation by downregulating TGF-ß/Smad signaling and that TGF-ß3 treatment was able to antagonize RA signaling. Transforming growth-interacting factor (TGIF) is a transcriptional repressor that suppresses both TGF-ß- and retinoid-driven gene transcription. Furthermore, we investigated the role of TGIF in the interaction between both TGF-ß and RA signaling in MEPM-cell proliferation. The results showed that both atRA and TGF-ß3 significantly increased the expression level of TGIF, and TGIF mediated the negative interaction between TGF-ß and RA signaling pathways, which depended on TGIF binding to Smad2 or RARß (RA receptor beta). Moreover, after deletion of TGIF, both the effects of atRA on TGF-ß-dependent protein expression and the effects of TGF-ß on RA-dependent protein expression were lost. So we conclude that there is a negative functional interplay of RA and TGF-ß signaling mediated by TGIF to modulate MEPM-cell proliferation.

Exploring the role and mechanism of hyperoside against cardiomyocyte injury in mice with myocardial infarction based on JAK2/STAT3 signaling pathway.

BACKGROUND: Myocardial infarction (MI) is one of the most deadly diseases in the world. Hyperoside (Hyp) has been shown to have a protective effect on cardiovascular function through various signaling pathways, but whether it can protect myocardial infarction by regulating JAK2/STAT3 signaling pathway is unknown. AIM OF THE STUDY: To investigate whether Hyp could protect the heart against myocardial infarction injury in mice by modulating JAK2/STAT3 signaling pathway and its potential mechanism. METHODS: In vivo experiments, the myocardial infarction model was established by ligating the left anterior descending coronary artery (LAD) of male C57BL/6 mice permanently. The mice were divided into seven groups: sham group, MI group, MI+Hyp (9 mg/kg), MI+Hyp (18 mg/kg) group, MI+Hyp (36 mg/kg) group, MI+Captopril group (15 mg/kg) group and MI+Hyp (36 mg/kg)+AG490 (7.5 mg/kg) group. Each group of animals were given different concentrations of hyperoside, positive control drug or inhibitor of JAK2/STAT3 singaling. After 14 days of administration, the electrocardiogram (ECG), echocardiography and serum myocardial injury markers were examined; Slices of mouse myocardial tissue were assessed for histopathological changes by HE, Masson and Sirius Red staining. TTC and TUNEL staining were used to evaluate the myocardial infarction area and cardiomyocytes apoptosis respectively. The expression of JAK2/STAT3 signaling pathway, apoptosis and autophagy-related proteins were detected by western blot. In vitro experiments, rat H9c2 cardiomyocytes were deprived of oxygen and glucose (OGD) to stimulate myocardial ischemia. The experiment was divided into seven groups: Control group, OGD group, OGD+Hyp (20 µM) group, OGD+Hyp (40 µM) group, OGD+Hyp (80 µM), OGD+Captopril (10 µM) group and OGD+Hyp (80 µM)+AG490 (100 µM) group. Myocardial cell damage and redox index were measured 12 h after OGD treatment. ROS content in cardiomyocytes was detected by immunofluorescence. Cardiomyocytes apoptosis was detected by flow cytometry. The expressions of JAK2/STAT3 signaling pathway-related proteins, apoptosis and autophagy related proteins were detected by western blot. RESULTS: In vivo, hyperoside could ameolirate ECG abnormality, increase cardiac function, reduce myocardial infarction size and significantly reduce myocardial fibrosis level and oxidation level. The experimental results in vitro showed that Hyp could reduce the ROS content in cardiomyocytes, decrease the level of oxidative stress and counteract the apoptosis induced by OGD injury . Both in vivo and in vitro experiments showed that hyperoside could increase phosphorylated JAK2 and STAT3, indicating that hyperoside could play a cardioprotective role by activating JAK2/STAT3 signaling pathway. It was also shown that hyperoside could increase the autophagy level of cardiomyocytes in vivo and in vitro. However the cardiomyocyte-protective effect of Hyp was abolished in combination with JAK2/ STAT3 signaling pathway inhibitor AG490. These results indicated that the protective effect of Hyp on cardiomyocyte injury was at least partially achieved through the activation of the JAK2/STAT3 signaling pathway. CONCLUSION: Hyp can significantly improve cardiac function, ameliorate myocardial hypertrophy and myocardial remodeling in MI mice. The mechanism may be related to improving mitochondrial autophagy of cardiomyocytes to maintain the advantage of autophagy, and blocking apoptosis pathway through phagocytosis, thus suppressing apoptosis level of cardiomyocytes. These effects of Hyp are achieved, at least in part, by activating the JAK2/STAT3 signaling pathway.

Construction of glutathione-responsive paclitaxel prodrug nanoparticles for image-guided targeted delivery and breast cancer therapy.

Paclitaxel (PTX) remains an essential drug in the treatment of breast cancer. To improve metabolic stability and real-time monitoring of drug location, we develop a visualized nano-prodrug. Novel hyaluronic acid (HA)-coated glutathione (GSH)-sensitive chitosan (CS)-based nano-prodrug (HA/TPE-CS-SS-PTX NPs) with aggregation-induced emission effects (AIE) were accomplished. The prodrug NPs (drug loading 29.32%, particle size 105 nm, regular sphericity) exhibit excellent fluorescence stability. The prodrug NPs could target tumor cells with high expression of CD44 and decompose in the presence of high concentrations of glutathione. In vitro evaluations revealed that the prodrug NPs have significant cytotoxicity on 4T1 cells, and due to their excellent AIE characteristics, their position in cells can be tracked. Moreover, the prodrug NPs also shown superior anti-tumor effects in vivo experimental. Overall, the HA/TPE-CS-SS-PTX NPs we constructed have excellent bio-imaging capabilities and can be served as a potential nanomedicine for PTX delivery against breast cancer.

Efficacy of polyethylene glycol loxenatide for type 2 diabetes mellitus patients: a systematic review and meta-analysis.

Objective: Some studies have proved that polyethylene glycol loxenatide (PEG-Loxe) has significant effects on controlling blood glucose and body weight in patients with type 2 diabetes mellitus (T2DM), but there is still some controversy over the improvement of blood lipid profiles (BLP) and blood pressure (BP), and more evidences are needed to verify such effects. Therefore, this study was conducted to provide a comprehensive evaluation of the efficacy of PEG-Loxe in improving blood glucose (BG), BLP, BP, body mass index (BMI), and body weight (BW) in patients with T2DM for clinical reference. Methods: Randomized controlled trials (RCT) in which PEG-Loxe was applied to treat T2DM were retrieved by searching PubMed, Cochrane Library, Embase, Medline, Scopus, Web of Science, China National Knowledge Infrastructure, China Scientific Journal, Wanfang Data, and SinoMed databases. Outcome measures included BG, BLP, BP, BMI, and BW. RevMan 5.3 software was used to perform data analysis. Results: Eighteen trials were identified involving 2,166 patients. In experimental group 1,260 patients received PEG-Loxe alone or with other hypoglycemic agents, while in control group 906 patients received placebo or other hypoglycemic agents. In the overall analysis, PEG-Loxe significantly reduced the levels of glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), 2-h postprandial blood glucose (2-h PBG), BMI, and BW compared with control group. However, it had no obvious effect on total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), systolic blood pressure (SBP), and diastolic blood pressure (DBP). Conclusion: PEG-Loxe has better hypoglycemic effects compared with placebo in patients with T2DM, but could not significantly improved TG, LDL-C, HDL-C, SBP, and DBP. And the combination of conventional hypoglycemic drugs (CHD) and PEG-Loxe could more effectively improve the levels of HbA1c, FPG, 2-h PBG, TC, TG, BMI, and BW compared with CHD in T2DM patients. Systematic Review Registration: www.inplasy.com, identifier INPLASY202350106.

Spermidine attenuates monocrotaline-induced pulmonary arterial hypertension in rats by inhibiting purine metabolism and polyamine synthesis-associated vascular remodeling.

Ensuring the homeostatic integrity of pulmonary artery endothelial cells (PAECs) is essential for combatting pulmonary arterial hypertension (PAH), as it equips the cells to withstand microenvironmental challenges. Spermidine (SPD), a potent facilitator of autophagy, has been identified as a significant contributor to PAECs function and survival. Despite SPD's observed benefits, a comprehensive understanding of its protective mechanisms has remained elusive. Through an integrated approach combining metabolomics and molecular biology, this study uncovers the molecular pathways employed by SPD in mitigating PAH induced by monocrotaline (MCT) in a Sprague-Dawley rat model. The study demonstrates that SPD administration (5 mg/kg/day) significantly corrects right ventricular impairment and pathological changes in pulmonary tissues following MCT exposure (60 mg/kg). Metabolomic profiling identified a purine metabolism disorder in MCT-treated rats, which SPD effectively normalized, conferring a protective effect against PAH progression. Subsequent in vitro analysis showed that SPD (0.8 mM) reduces oxidative stress and apoptosis in PAECs challenged with Dehydromonocrotaline (MCTP, 50 µM), likely by downregulating purine nucleoside phosphorylase (PNP) and modulating polyamine biosynthesis through alterations in S-adenosylmethionine decarboxylase (AMD1) expression and the subsequent production of decarboxylated S-adenosylmethionine (dcSAM). These findings advocate SPD's dual inhibitory effect on PNP and AMD1 as a novel strategy to conserve cellular ATP and alleviate oxidative injuries, thus providing a foundation for SPD's potential therapeutic application in PAH treatment.

Synthesis and chirality control of bulk crystals and nanocrystals: from a right-handed nonpolar chain to a left-handed polar chain.

Both bulk crystals and nanocrystals of two helical complexes, [Cu(µ2-L)(H2O)]n (1) and {[Cu(µ2-L)(H2O)]·2H2O}n (2) (H2L = thiazolidine-2,4-dicarboxylic acid), have been synthesized with the chiralities of right-handedness (1) and left-handedness (2), respectively. 4-Cyanopyridine and poly(vinylpyrrolidone) (PVP) have been applied to control the synthesis of complexes with different helicities in bulk-crystal and nanocrystal forms, respectively. 2 can be irreversibly transformed to 1 under heating. Associated with the conformation changing, the symmetry alters between nonpolar and polar space groups.