Impairment of the Vascular KATP Channel Imposes Fatal Susceptibility to Experimental Diabetes Due to Multi-Organ Injuries.

The vascular isoform of ATP-sensitive K(+) (KATP ) channels regulates blood flow to all organs. The KATP channel is strongly inhibited by reactive oxygen and carbonyl species produced in diabetic tissue inflammation. To address how such channel inhibition impacts vascular regulation as well as tissue viability, we performed studies in experimental diabetic mice. Strikingly, we found that knockout of the Kcnj8 encoding Kir6.1 subunit (Kcnj8-KO) caused mice to be fatally susceptible to diabetes. Organ perfusion studies suggested that the lack of this vascular K(+) channel handicapped activity-dependent vasodilation, leading to hypoperfusion, tissue hypoxia, and multi-organ failure. Morphologically, Kcnj8-KO mice showed greater inflammatory cell infiltration, higher levels of expression of inflammation indicator proteins, more severe cell apoptosis, and worse tissue disruptions. These were observed in the kidney, liver, and heart under diabetic condition in parallel comparison to tissues from WT mice. Patch clamping and molecular studies showed that the KATP channel was S-glutathionylated in experimental diabetes contributing to the inhibition of channel activity as well as the reduced arterial responses to vasodilators. These results suggest that the vascular KATP channel is organ protective in diabetic condition, and since the channel is suppressed by diabetic oxidative stress, therapeutical interventions to the maintenance of functional KATP channels may help to lower or prevent diabetic organ dysfunction.

Phytochemistry and pharmacology of Armeniacae semen Amarum: A review.

ETHNOPHARMACOLOGICAL RELEVANCE: Armeniacae Semen Amarum (Prunus armeniaca L. var. ansu Maxim., Ku xingren, bitter almond, ASA) is an important medicine in Traditional Chinese Medicine (TCM). It is widely used because of its remarkable curative effect in relieving cough and asthma, moistening intestines and defecating. AIM OF THE REVIEW: This review aims to enlighten the deeper knowledge about ASA, giving a comprehensive overview of its traditional uses, phytochemistry, pharmacology and toxicology for future investigation of plant-based drugs and therapeutic applications. MATERIALS AND METHODS: The databases used are Web of Science, PubMed, Baidu academic, Google academic, CNKI, Wanfang and VIP . In addition, detailed information on ASA was obtained from relevant monographs such as Chinese Pharmacopoeia. RESULTS: The active components of ASA mainly include amygdalin, bitter almond oil, essential oil, protein, vitamin, trace elements and carbohydrates. The pharmacological studies have shown that ASA has beneficial effects such as antitussive, antiasthmatic, anti-inflammatory, analgesic, antioxidant, antitumour, cardioprotective, antifibrotic, immune regulatory, bowel relaxation, insecticidal, etc. CONCLUSIONS: Many reports have been published on ASA's various active ingredients and biological uses. However, only a few reviews on its phytoconstituents and pharmacological uses. In addition, the exploration and development of ASA in other fields also deserve more attention in future research.

Anti-apoptotic protein BCL-XL as a therapeutic vulnerability in gastric cancer.

BACKGROUND: New therapeutic targets are needed to improve the outcomes for gastric cancer (GC) patients with advanced disease. Evasion of programmed cell death (apoptosis) is a hallmark of cancer cells and direct induction of apoptosis by targeting the pro-survival BCL2 family proteins represents a promising therapeutic strategy for cancer treatment. Therefore, understanding the molecular mechanisms underpinning cancer cell survival could provide a molecular basis for potential therapeutic interventions. METHOD: Here we explored the role of BCL2L1 and the encoded anti-apoptotic BCL-XL in GC. Using Droplet Digital PCR (ddPCR) technology to investigate the DNA amplification of BCL2L1 in GC samples and GC cell lines, the sensitivity of GC cell lines to selective BCL-XL inhibitors A1155463 and A1331852, pan-inhibitor ABT-263, and VHL-based PROTAC-BCL-XL was analyzed using (CellTiter-Glo) CTG assay in vitro. Western Blot (WB) was used to detect the protein expression of BCL2 family members in GC cell lines and the manner in which PROTAC-BCL-XL kills GC cells. Co-immunoprecipitation (Co-IP) was used to investigate the mechanism of A1331852 and ABT-263 kills GC cell lines. DDPCR, WB, and real-time PCR (RTPCR) were used to investigate the correlation between DNA, RNA, protein levels, and drug activity. RESULTS: The functional assay showed that a subset of GC cell lines relies on BCL-XL for survival. In gastric cancer cell lines, BCL-XL inhibitors A1155463 and A1331852 are more sensitive than the pan BCL2 family inhibitor ABT-263, indicating that ABT-263 is not an optimal inhibitor of BCL-XL. VHL-based PROTAC-BCL-XL DT2216 appears to be active in GC cells. DT2216 induces apoptosis of gastric cancer cells in a time- and dose-dependent manner through the proteasome pathway. Statistical analysis showed that the BCL-XL protein level predicts the response of GC cells to BCL-XL targeting therapy and BCL2L1 gene CNVs do not reliably predict BCL-XL expression. CONCLUSION: We identified BCL-XL as a promising therapeutic target in a subset of GC cases with high levels of BCL-XL protein expression. Functionally, we demonstrated that both selective BCL-XL inhibitors and VHL-based PROTAC BCL-XL can potently kill GC cells that are reliant on BCL-XL for survival. However, we found that BCL2L1 copy number variations (CNVs) cannot reliably predict BCL-XL expression, but the BCL-XL protein level serves as a useful biomarker for predicting the sensitivity of GC cells to BCL-XL-targeting compounds. Taken together, our study pinpointed BCL-XL as potential druggable target for specific subsets of GC.

Advances in extraction methods, chemical constituents, pharmacological activities, molecular targets and toxicology of volatile oil from Acorus calamus var. angustatus Besser.

Acorus calamus var. angustatus Besser (ATT) is a traditional herb with a long medicinal history. The volatile oil of ATT (VOA) does possess many pharmacological activities. It can restore the vitality of the brain, nervous system and myocardial cells. It is used to treat various central system, cardiovascular and cerebrovascular diseases. It also showed antibacterial and antioxidant activity. Many studies have explored the benefits of VOA scientifically. This paper reviews the extraction methods, chemical components, pharmacological activities and toxicology of VOA. The molecular mechanism of VOA was elucidated. This paper will serve as a comprehensive resource for further carrying the VOA on improving its medicinal value and clinical use.

Diallyl Trisulfide Suppresses High-Glucose-Induced Cardiomyocyte Apoptosis by Targeting Reactive Oxygen Species-Mediated Hypoxia-Inducible Factor-1α/Insulin-like Growth Factor Binding Protein 3 Activation.

It has been reported that 80% of diabetic patients die due to cardiovascular diseases. We previously demonstrated that activated hypoxia-inducible factor-1α (HIF-1 α)/insulin-like growth factor binding protein-3 (IGFBP-3) signaling by reactive oxygen species (ROS)-regulated prolyl hydroxylase domain-containing protein (PHD) is involved in high-glucose (HG)-induced cardiac apoptosis. Diallyl trisulfide (DATS), a garlic component, shows the strongest inhibitory effect on diabetic cardiomyopathy. In this study, we investigated whether HIF-1α/IGFBP-3 signaling governs the antiapoptotic effect by DATS on HG-exposed cardiomyocytes. It was observed that significantly increased levels of cell apoptosis and decreased Akt phosphorylation were reversed by DATS in HG-exposed cardiac cells. H2O2 and PHD small interfering RNA treatments increased HIF-1α and IGFBP-3 protein levels, which were decreased by DATS treatment. Overexpression of HIF-1α and IGFBP-3 increased HG-induced cell apoptosis, which was suppressed by DATS. The coimmunoprecipitation assay results showed that DATS not only increased the IGF-1 level and reduced IGFBP-3 level but also suppressed their extracellular association for cardiac cells exposed to HG. Experiments using neonatal cardiomyocytes and hearts showed similar results. These findings indicate that the effect of ROS-regulated PHD on the activation of HIF-1α/IGFBP-3 signaling governs the antiapoptotic effect by DATS on HG-exposed cardiomyocytes.

A novel label-free strategy for the ultrasensitive miRNA-182 detection based on MoS2/Ti3C2 nanohybrids.

MicroRNAs (miRNAs) are regarded as a large variety of cancer-related biomarkers, and they have attracted wide attentions in recent years. In this work, a novel label-free strategy for the ultrasensitive detection of miRNA-182 (a typical biomarker for lung cancer) based on MoS2/Ti3C2 nanohybrids was suggested. Firstly, modified glassy carbon electrode (GCE) with massive active sites and good electronic conductivity was prepared for biosensing. Then, based on this platform a descent signal in differential pulse voltammetry (DPV) peak current could be observed with the addition of probe RNA with negative charge. Thereafter, with the hybridization of target miRNA-182 with immobilized probe RNA and the swelling-induced breakage of Au-S bonds between RNA and the electrode surface, the characteristic DPV signals increase were found. In particular, this biosensing platform for special miRNAs possessed a good linear detection window in a range from 1 fM to 0.1 nM with a detection limit of 0.43 fM.

Ultrasensitive detection of miRNA-155 based on controlled fabrication of AuNPs@MoS2 nanostructures by atomic layer deposition.

MicroRNA-155 (miRNA-155) is a typical cancer-related biomarker, which often exists at ultralow concentrations in the plasma or body fluids of early patients. In this work, a novel label-free platform for ultrasensitive miRNA-155 detection was designed based on the precise fabrication of molybdenum disulfide (MoS2) by atomic layer deposition (ALD). Au nanoparticles (AuNPs)@MoS2 nanostructures were the core parts for the detection electrode, and the measurement precision of the sensing platform was modulated and optimized by ALD-based thickness and shape control of ultrathin MoS2 nanoflakes (thickness: ~14 nm, about 20 layers, uniform continuous distribution). In the detection experiment, MoS2 nanoflakes served as a conductive skeleton to support more AuNPs, and the results showed that the effective control of their morphology and thickness was of vital importance for ultrasensitive acquisition of detection signals. With using toluidine blue (TB) as a hybridization indicator, ultrasensitive detection record ranging from 1 fM to 10 nM with a detection limit of 0.32 fM can be achieved.

Using a Mixed Model to Explore Evaluation Criteria for Bank Supervision: A Banking Supervision Law Perspective.

Financial supervision means that monetary authorities have the power to supervise and manage financial institutions according to laws. Monetary authorities have this power because of the requirements of improving financial services, protecting the rights of depositors, adapting to industrial development, ensuring financial fair trade, and maintaining stable financial order. To establish evaluation criteria for bank supervision in China, this study integrated fuzzy theory and the decision making trial and evaluation laboratory (DEMATEL) and proposes a fuzzy-DEMATEL model. First, fuzzy theory was applied to examine bank supervision criteria and analyze fuzzy semantics. Second, the fuzzy-DEMATEL model was used to calculate the degree to which financial supervision criteria mutually influenced one another and their causal relationship. Finally, an evaluation criteria model for evaluating bank and financial supervision was established.

Diallyl trisulfide protects against high glucose-induced cardiac apoptosis by stimulating the production of cystathionine gamma-lyase-derived hydrogen sulfide.

BACKGROUND: Cystathionine-γ-lyase (CSE)-derived hydrogen sulfide (H2S) is a potent cardioprotective agent. We investigated the effects of diallyl trisulfide (DATS) on CSE expression and H2S generation in myocardium and examined whether DATS-mediated H2S generation effectively protects rat heart from diabetes-induced cardiac damage. METHODS: The correlations between the effects of hyperglycemia and diabetes on CSE expression and the effects of DATS and H2S on hyperglycemia and diabetes were examined in vitro in the cardiomyocyte cell line H9c2 and in vivo in hearts from rats with streptozotocin-induced diabetes mellitus (DM). RESULTS: Expression of CSE, a catalyst of H2S production, was suppressed in H9c2 cells treated with high glucose (33 mM) and in DM rat hearts. CSE suppression also correlated with a decrease in the activation of the pro-survival protein kinase Akt. Treatment of H9c2 cells with DATS resulted in increased CSE expression and a reduction in apoptosis via a mechanism involving IGF1R/pAkt signaling and by modulating the expression of reactive oxygen species-related enzymes. The role CSE plays in the cardioprotective effects of DATS was further confirmed by CSE inhibition assays including inhibitors and siRNA. CONCLUSION: DATS produces H2S as efficiently as NaSH and DATS-derived H2S provides effective cardioprotection. Further, our data indicate that H2S plays a major role in the protective effect of DATS against apoptosis of cardiomyocytes.