Connexin32 gap junction channels deliver miR155-3p to mediate pyroptosis in renal ischemia-reperfusion injury.

OBJECTIVES: To explore whether the gap junction (GJ) composed by connexin32(Cx32) mediated pyroptosis in renal ischemia-reperfusion(I/R) injury via transmitting miR155-3p, with aim to provide new strategies for the prevention and treatment of acute kidney injury (AKI) after renal I/R. METHODS: 8-10 weeks of male C57BL/ 6 wild-type mice and Cx32 knockdown mice were divided into two groups respectively: control group and renal I/R group. MCC950 (50 mg/kg. ip.) was used to inhibit NLRP3 in vivo. Human kidney tubular epithelial cells (HK - 2) and rat kidney tubular epithelial cells (NRK-52E) were divided into high-density group and low-density group, and treated with hypoxia reoxygenation (H/R) to mimic I/R. The siRNA and plasmid of Cx32, mimic and inhibitor of miR155-3p were transfected into HK - 2 cells respectively. Kidney pathological and functional injuries were measured. Western Blot and immunofluorescent staining were used to observe the expression of NLRP3, GSDMD, GSDMD-N, IL - 18, and mature IL-18. The secretion of IL-18 and IL-1ß in serum, kidney tissue and cells supernatant were detected by enzyme-linked immuno sorbent assay (ELISA) kit, and the expression of NLPR3 and miR155-3p were detected by RT-qPCR and fluorescence in situ hybridization (FISH). RESULTS: Tubular pyroptosis were found to promote AKI after I/R in vivo and Cx32-GJ regulated pyroptosis by affecting the expression of miR155-3p after renal I/R injury. In vitro, H/R could lead to pyroptosis in HK-2 and NRK-52E cells. When the GJ channels were not formed, and Cx32 was inhibited or knockdown, the expression of miR155-3p was significantly reduced and the pyroptosis was obviously inhibited, leading to the reduction of injury and the increase of survival rate. Moreover, regulating the level of miR155-3p could affect survival rate and pyroptosis in vitro after H/R. CONCLUSIONS: The GJ channels composed of Cx32 regulated tubular pyroptosis in renal I/R injury by transmitting miR155-3p. Inhibition of Cx32 could reduce the level of miR155-3p further to inhibit pyroptosis, leading to alleviation of renal I/R injury which provided a new strategy for preventing the occurrence of AKI. Video Abstract.

Next-generation fungal identification using target enrichment and Nanopore sequencing.

BACKGROUND: Rapid and accurate pathogen identification is required for disease management. Compared to sequencing entire genomes, targeted sequencing may be used to direct sequencing resources to genes of interest for microbe identification and mitigate the low resolution that single-locus molecular identification provides. This work describes a broad-spectrum fungal identification tool developed to focus high-throughput Nanopore sequencing on genes commonly employed for disease diagnostics and phylogenetic inference. RESULTS: Orthologs of targeted genes were extracted from 386 reference genomes of fungal species spanning six phyla to identify homologous regions that were used to design the baits used for enrichment. To reduce the cost of producing probes without diminishing the phylogenetic power, DNA sequences were first clustered, and then consensus sequences within each cluster were identified to produce 26,000 probes that targeted 114 genes. To test the efficacy of our probes, we applied the technique to three species representing Ascomycota and Basidiomycota fungi. The efficiency of enrichment, quantified as mean target coverage over the mean genome-wide coverage, ranged from 200 to 300. Furthermore, enrichment of long reads increased the depth of coverage across the targeted genes and into non-coding flanking sequence. The assemblies generated from enriched samples provided well-resolved phylogenetic trees for taxonomic assignment and molecular identification. CONCLUSIONS: Our work provides data to support the utility of targeted Nanopore sequencing for fungal identification and provides a platform that may be extended for use with other phytopathogens.

Comparative Genomics of Fusarium circinatum Isolates Used to Screen Southern Pines for Pitch Canker Resistance.

Pitch canker, caused by the fungal pathogen Fusarium circinatum, is a global disease affecting many Pinus spp. Often fatal, this disease causes significant mortality in both commercially grown and natural pine forests and is an issue of current and growing concern. F. circinatum isolates collected from three locations in the U.S. state of Florida were shown to be virulent on both slash and loblolly pine, with two of the isolates causing equivalent and significantly larger lesions than those caused by the third isolate during pathogenicity trials. In addition, significant genetic variation in lesion length in the pedigreed slash pine population was evident and rankings of parents for lesion length were similar across isolates. Experimental data demonstrate that both host and pathogen genetics contribute to disease severity. High-quality genomic assemblies of all three isolates were created and compared for structural differences and gene content. No major structural differences were observed among the isolates; however, missing or altered genes do contribute to genomic variation in the pathogen population. This work evaluates in planta virulence among three isolates of F. circinatum, provides genomic resources to facilitate study of this organism, and details comparative genomic methods that may be used to explore the pathogen's contribution to disease development.[Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

The effect of Sirt1 deficiency on Ca2+ and Na+ regulation in mouse ventricular myocytes.

This study addressed the hypothesis that cardiac Sirtuin 1 (Sirt1) deficiency alters cardiomyocyte Ca2+ and Na+ regulation, leading to cardiac dysfunction and arrhythmogenesis. We used mice with cardiac-specific Sirt1 knockout (Sirt1-/- ). Sirt1flox/flox mice were served as control. Sirt1-/- mice showed impaired cardiac ejection fraction with increased ventricular spontaneous activity and burst firing compared with those in control mice. The arrhythmic events were suppressed by KN93 and ranolazine. Reduction in Ca2+ transient amplitudes and sarcoplasmic reticulum (SR) Ca2+ stores, and increased SR Ca2+ leak were shown in the Sirt1-/- mice. Electrophysiological measurements were performed using patch-clamp method. While L-type Ca2+ current (ICa, L ) was smaller in Sirt1-/- myocytes, reverse-mode Na+ /Ca2+ exchanger (NCX) current was larger compared with those in control myocytes. Late Na+ current (INa, L ) was enhanced in the Sirt1-/- mice, alongside with elevated cytosolic Na+ level. Increased cytosolic and mitochondrial reactive oxygen species (ROS) were shown in Sirt1-/- mice. Sirt1-/- cardiomyocytes showed down-regulation of L-type Ca2+ channel α1c subunit (Cav1.2) and sarcoplasmic/endoplasmic reticulum Ca2+  ATPase 2a (SERCA2a), but up-regulation of Ca2+ /calmodulin-dependent protein kinase II and NCX. In conclusions, these findings suggest that deficiency of Sirt1 impairs the regulation of intracellular Ca2+ and Na+ in cardiomyocytes, thereby provoking cardiac dysfunction and arrhythmogenesis.

The glutathione peroxidase-mediated reactive oxygen species resistance, fungicide sensitivity and cell wall construction in the citrus fungal pathogen Alternaria alternata.

The ability to detoxify reactive oxygen species (ROS) is critical for pathogenicity in the necrotrophic fungus Alternaria alternata. We report a glutathione peroxidase 3 (AaGPx3) involved in the complex signalling network that is essential for the detoxification of cellular stresses induced by ROS and for A. alternata pathogenesis in citrus. AaGPx3 deletion mutants displayed increased sensitivity to H2 O2 and many ROS-generating compounds. AaGPx3 is required for correct fungal development as the AaGPx3 mutant strains showed a severe reduction in conidiation. AaGPx3 mutants accumulated higher chitin content than the wild-type and were less sensitive to the cell wall-targeting compounds calcofluor white and Congo red, as well as the fungicides fludioxonil and vinclozolin, suggesting a role of the glutathione systems in fungal cell wall construction. Virulence assays revealed that AaGPx3 is required for full virulence. The expression of AaGPx3 was downregulated in fungal strains carrying defective NADPH oxidase (Nox) or the oxidative stress responsive regulators YAP1 and HOG1, all implicated in ROS resistance. These results further support the important role of ROS detoxification during A. alternata pathogenesis in citrus. Overall, our study provides genetic evidence to define the central role of AaGPx3 in the biological and pathological functions of A. alternata.

Hydrogen Sulfide Modulates the S-Nitrosoproteome and the Mitochondrial Morphology in Endothelial Cells.

BACKGROUND: Hydrogen sulfide (H2S) is one of the endogenous gaseous molecules promoting the production of nitric oxide (NO) which has cardioprotective functions. However, the role of the H2S-mediated protein S-nitrosoproteome and its subsequent physiological response remains unclear. METHODS: Endothelial cells EAhy 926 were treated with 50 µM of H2S for 2 hours. The NO bound S-nitrosoproteins were purified by a biotin-switch and then digested by trypsin. Resulting peptides from control and H2S treatment were separately labeled by isobaric tag for relative and absolute quantitation 114/115, quantified by liquid chromatography tandem-mass spectrometry and analyzed by ingenuity pathway analysis (IPA) software. The microP software was applied to analyze the morphological changes of mitochondria. RESULTS: With the treatment of H2S, 416 S-nitrosylated proteins were identified. IPA analysis showed that these proteins were involved in five signaling pathways. The NO-bound cysteine residues and the S-nitrosylation levels (115/114) were shown for ten S-nitrosoproteins. Western blot further verified the S-nitrosylation of thioredoxin-dependant peroxide reductase, cytochrome c oxidase and cytochrome b-c1 complex that are involved in the mitochondrial signaling pathway. H2O2-induced mitochondrial swelling can be reduced by the pretreatment of H2S. CONCLUSIONS: The H2S-mediated endothelial S-nitrosoproteome has been confirmed. In the present study, we have proposed the cardioprotective role of H2S via maintaining mitochondrial homeostasis.

Dapagliflozin in heart failure and type 2 diabetes: Efficacy, cardiac and renal effects, safety.

BACKGROUND: Heart failure (HF), especially HF with reduced ejection fraction (HFrEF), presents complex challenges, particularly in the aging population where it often coexists with type 2 diabetes mellitus (T2DM). AIM: To analyze the effect of dapagliflozin treatment on cardiac, renal function, and safety in patients with HFrEF combined with T2DM. METHODS: Patients with T2DM complicated with HFrEF who underwent treatment in our hospital from February 2018 to March 2023 were retrospectively analyzed as the subjects of this study. The propensity score matching method was used, and a total of 102 eligible samples were scaled. The clinical efficacy of the two groups was evaluated at the end of the treatment, comparing the results of blood glucose, insulin, cardiac function, markers of myocardial injury, renal function indexes, and 6-min walk test (6MWT) before and after the treatment. We compared the occurrence of adverse effects on the treatment process of the two groups of patients. The incidence of adverse outcomes in patients within six months of treatment was counted. RESULTS: The overall clinical efficacy rate of patients in the study group was significantly higher than that of patients in the control group (P = 0.013). After treatment, the pancreatic beta-cell function index, left ventricular ejection fraction, and glomerular filtration rate of patients in the study group were significantly higher than control group (P < 0.001), while their fasting plasma glucose, 2-h postprandial glucose, glycosylated hemoglobin, insulin resistance index, left ventricular end-systolic diameter, left ventricular end-diastolic diameter, cardiac troponin I, creatine kinase-MB, N-terminal pro b-type natriuretic peptide, serum creatinine, and blood urea nitrogen were significantly lower than those of the control group. After treatment, patients in the study group had a significantly higher 6MWT than those in the control group (P < 0.001). Hypoglycemic reaction (P = 0.647), urinary tract infection (P = 0.558), gastrointestinal adverse effect (P = 0.307), respiratory disturbance (P = 0.558), and angioedema (P = 0.647) were not statistically different. There was no significant difference between the incidence of adverse outcomes between the two groups (P = 0.250). CONCLUSION: Dapagliflozin significantly enhances clinical efficacy, cardiac and renal function, and ambulatory capacity in patients with HFrEF and T2DM without an increased risk of adverse effects or outcomes.

Preparation techniques, structural features, and bioactivities of Eucommia ulmoides polysaccharides: A review.

Eucommia ulmoides Oliv. (tu-chung), as a famous nature medical and edible plant, has the effect of tonifying liver and kidney, strengthening the function of the muscles and bones, and miscarriage prevention. Accumulating evidence has demonstrated that the polysaccharides from Eucommia ulmoides Oliv. (EUPs) are a kind of vital and representative biologically active macromolecules and have various health-promoting biological activities in vivo and in vitro, such as antioxidant activity, immunomodulatory activity, hypolipidemic and hypoglycemic activities, anti-inflammatory activities, anti-tumor activity, and among others. The review aims to comprehensively and systematically collate the recent research progress on extraction and purification methods, structural characteristics, biological activities, mechanism of action, structural modification, and toxicity of EUPs to support their therapeutic potential and health-care functions. New valuable insights for future research with EUPs were also proposed in the areas of structural characterization and pharmacological activities to promoting the development of therapeutic agents and functional foods.

Genome sequencing and de novo assembly of Trichoderma longibrachiatum isolate collected from Florida agricultural soils.

We report a draft genome assembly of Trichoderma longibrachiatum isolate GEV 3550, obtained from Florida, United States of America.

Association Between the Red Blood Cell Distribution Width and 30-Day Mortality in Intensive Care Patients Undergoing Cardiac Surgery: A Retrospective Observational Study Based on the Medical Information Mart for Intensive Care-IV Database.

Background: Millions of patients undergo cardiac surgery each year. The red blood cell distribution width (RDW) could help predict the prognosis of patients who undergo percutaneous coronary intervention or coronary artery bypass surgery. We investigated whether the RDW has robust predictive value for the 30-day mortality among patients in an intensive care unit (ICU) after undergoing cardiac surgery. Methods: Using the Medical Information Mart for Intensive Care-IV Database, we retrieved data for 11,634 patients who underwent cardiac surgery in an ICU. We performed multivariate Cox regression analysis to model the association between the RDW and 30-day mortality and plotted Kaplan-Meier curves. Subgroup analyses were stratified using relevant covariates. Receiver operating characteristic (ROC) curves were used to determine the predictive value of the RDWs. Results: The total 30-day mortality rate was 4.2% (485/11,502). The elevated-RDW group had a higher 30-day mortality rate than the normal-RDW group (P&0.001). The robustness of our data analysis was confirmed by performing subgroup analyses. Each unit increase in the RDW was associated with a 17% increase in 30-day mortality when the RDW was used as a continuous variable (adjusted hazard ratio=1.17, 95% confidence interval, 1.10-1.25). Our ROC results showed the predictive value of the RDW. Conclusions: An elevated RDW was associated with a higher 30-day mortality in patients after undergoing cardiac surgery in an ICU setting. The RDW can serve as an efficient and accessible method for predicting the mortality of patients in ICUs following cardiac surgery.

Polysaccharides from Spirulina platensis: Extraction methods, structural features and bioactivities diversity.

Spirulina platensis, a well-known blue-green microalga cultivated and consumed in China and United States, is traditionally used as a food supplement and medical ingredient. Increasing evidence has confirmed that the Spirulina platensis polysaccharides (SPPs) are vital and representative pharmacologically active biomacromolecules and exhibit multiple health-promoting activities both in vivo and in vitro, such as those of anti-cancer, anti-oxidant, immunomodulatory, hypolipidemic and hypoglycemic, anti-thrombotic, anti-viral, regulation of the gut microbiota properties and other biological activity. The purpose of this review aims to comprehensively and systematically outline the extraction and purification methods, structural features, biological activities, underlying mechanisms, and toxicities of SPPs to support their potential utilization value in pharmaceuticals fields and functional foods. The structural and activities relationship of SPPs is also discussed. Besides, new valuable insights for future research with SPPs have also been proposed in the important areas of structural characterization and pharmacological activities.

Advancing the automation of plant nucleic acid extraction for rapid diagnosis of plant diseases in space.

Human space exploration missions will continue the development of sustainable plant cultivation in what are obviously novel habitat settings. Effective pathology mitigation strategies are needed to cope with plant disease outbreaks in any space-based plant growth system. However, few technologies currently exist for space-based diagnosis of plant pathogens. Therefore, we developed a method of extracting plant nucleic acid that will facilitate the rapid diagnosis of plant diseases for future spaceflight applications. The microHomogenizer™ from Claremont BioSolutions, originally designed for bacterial and animal tissue samples, was evaluated for plant-microbial nucleic acid extractions. The microHomogenizer™ is an appealing device in that it provides automation and containment capabilities that would be required in spaceflight applications. Three different plant pathosystems were used to assess the versatility of the extraction process. Tomato, lettuce, and pepper plants were respectively inoculated with a fungal plant pathogen, an oomycete pathogen, and a plant viral pathogen. The microHomogenizer™, along with the developed protocols, proved to be an effective mechanism for producing DNA from all three pathosystems, in that PCR and sequencing of the resulting samples demonstrated clear DNA-based diagnoses. Thus, this investigation advances the efforts to automate nucleic acid extraction for future plant disease diagnosis in space.

The cAMP-dependent protein kinase A pathway perturbs autophagy and plays important roles in development and virulence of Sclerotinia sclerotiorum.

Previous research has demonstrated that sclerotia production is suppressed by exogenous cyclic AMP (cAMP) in Sclerotinia sclerotiorum and enhanced upon deletion of the adenylate cyclase gene. This study focuses on further functionally characterizing the cAMP-dependent protein kinase A (PKA) signaling pathway in S. sclerotiorum. Here, we demonstrate functions for two components of cAMP signaling: the catalytic, SsPKA, and the regulatory, SsPKAR, subunits of cAMP-dependent PKA. Growth and virulence were greatly reduced by disruption of either Sspka2 or SspkaR in addition to deficiencies in appressorium development. Surprisingly, disruption of both Sspka2 (dSspka2) and SspkaR (dSspkaR) display an up-regulation of autophagy without nutrient starvation suggesting that properly regulated PKA activity is required for control of autophagy. SsPKAR is demonstrated to be required for carbohydrate metabolism and mobilization, which are required for appressorium development and sclerotium initiation. A closer examination of dSspkaR during Nicotiana benthamiana infection revealed that an oxalic acid (OA)-independent necrosis protein(s) or metabolite(s) may be involved in the lesion development in dSspkaR-N. benthamiana interaction. In summary, these data demonstrate that the cAMP-dependent PKA signaling is essential for multiple forms of S. sclerotiorum development as well as virulence which rely on optimal regulation of autophagy.

Berberis dictyophylla F. inhibits angiogenesis and apoptosis of diabetic retinopathy via suppressing HIF-1α/VEGF/DLL-4/Notch-1 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Xiao Bopi (XBP, སྐྱེར་བའི་བར་ཤུན།), as a classical Tibetan medicinal plant in China, which derived from the stem bark of Berberis dictyophylla F., has the function of "clearing heat and decreasing mKhris-pa". And it traditionally is utilized to treat the diabetes mellitus and its complications, such as diabetic retinopathy (DR). However, its underlying mechanisms remain unclear. AIM OF THE STUDY: The purpose of this study aimed to explore the microvascular protection of water extract of XBP against the spontaneous retinal damage of db/db mice. Meanwhile, the underlying mechanisms of XBP on angiogenesis and apoptosis were further interpreted. MATERIALS AND METHODS: We firstly used high-performance liquid chromatography to detected the representative chemical ingredients in the water extract of XBP. The DR model of db/db mice was then randomly divided into five groups: model group, calcium dobesilate (0.23 g/kg) group, and the water extract of XBP (0.375, 0.75 and 1.5 g/kg, respectively) groups. After 8 weeks of continuous administration, the parameters including body weight, fasting blood glucose, oral glucose tolerance test and insulin tolerance test were measured. The pathological changes and abnormal angiogenesis of the retina were detected by optical coherence tomography, HE, periodic acid-Schiff staining and transmission electron microscopy. Simultaneously, molecular docking was used to predict the potential connections between representative ingredients in XBP and angiogenesis/apoptosis-related proteins. The level of angiogenesis-related proteins and gene hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth (VEGF), delta-like ligand 4 (DLL-4) and Notch-1 were estimated by immunofluorescence analyses and real time-PCR. Further, TUNEL staining and immunofluorescence analyses were performed to investigate the apoptotic phenomenon and the expression of Bax, Bcl-2, Apaf-1, Cyto-c and cleaved caspase-3 and cleaved caspase-9 in the retina. RESULTS: Phytochemical analysis revealed that magnoflorine, jatrorrhizine, palmatine and berberine were principally representative ingredients in XBP. The results demonstrated that XBP effectively increased glucose tolerance and insulin sensitivity, whereas no effect on body weight of DR mice. Moreover, retinal thickening, pathological and retinal ultrastructure changes in DR mice were evidently ameliorated by XBP. The molecular docking results demonstrated that the main components of XBP and the protein of angiogenesis and apoptosis had a potential bind. XBP restrained the gene and protein levels of HIF-1α, VEGF, DLL-4 and Notch-1 in retina. Additionally, the TUNEL-positive cell rate and the down-regulated proteins of Bax, Apaf-1, Cyto-c, cleaved Caspase-3 and cleaved Caspase 9 and increased Bcl-2 level were revised by XBP. CONCLUSIONS: To sum up, the results suggested that XBP against DR could attribute to alleviating angiogenesis and apoptosis by suppressing the HIF-1α/VEGF/DLL-4/Notch-1 pathway. This evidence sheds a new light on the potential mechanisms of XBP in the treatment of DR.

The Role of Sirtuin 1 in Palmitic Acid-Induced Endoplasmic Reticulum Stress in Cardiac Myoblasts.

BACKGROUND: Lipotoxicity causes endoplasmic reticulum (ER) stress, leading to cell apoptosis. Sirtuin 1 (Sirt1) regulates gene transcription and cellular metabolism. In this study, we investigated the role of Sirt1 in palmitate-induced ER stress. METHODS: Both H9c2 myoblasts and heart-specific Sirt1 knockout mice fed a palmitate-enriched high-fat diet were used. RESULTS: The high-fat diet induced C/EBP homologous protein (CHOP) and activating transcription factor 4 (ATF4) expression in both Sirt1 knockout mice and controls. The Sirt1 knockout mice showed higher CHOP and ATF4 expression compared to those in the control. Palmitic acid (PA) induced ATF4 and CHOP expression in H9c2 cells. PA-treated H9c2 cells showed decreased cytosolic NAD+/NADH alongside reduced Sirt1's activity. The H9c2 cells showed increased ATF4 and CHOP expression when transfected with plasmid encoding dominant negative mutant Sirt1. Sirt1 activator SRT1720 did not affect CHOP and ATF4 expression. Although SRT1720 enhanced the nuclear translocation of ATF4, the extent of the binding of ATF4 to the CHOP promoter did not increase in PA treated-H9c2 cells. CONCLUSION: PA-induced ER stress is mediated through the upregulation of ATF4 and CHOP. Cytosolic NAD+ concentration is diminished by PA-induced ER stress, leading to decreased Sirt1 activity. The Sirt1 activator SRT1720 promotes the nuclear translocation of ATF4 in PA-treated H9c2 cells.

Draft Genome Sequence and De Novo Assembly of a Fusarium oxysporum f. sp. lycopersici Isolate Collected from the Andean Region in Colombia.

We report a draft genome assembly of the causal agent of tomato vascular wilt, Fusarium oxysporum f. sp. lycopersici isolate 59, obtained from the Andean region in Colombia.

Berberine: A Review of its Pharmacokinetics Properties and Therapeutic Potentials in Diverse Vascular Diseases.

Traditional Chinese medicine plays a significant role in the treatment of various diseases and has attracted increasing attention for clinical applications. Vascular diseases affecting vasculature in the heart, cerebrovascular disease, atherosclerosis, and diabetic complications have compromised quality of life for affected individuals and increase the burden on health care services. Berberine, a naturally occurring isoquinoline alkaloid form Rhizoma coptidis, is widely used in China as a folk medicine for its antibacterial and anti-inflammatory properties. Promisingly, an increasing number of studies have identified several cellular and molecular targets for berberine, indicating its potential as an alternative therapeutic strategy for vascular diseases, as well as providing novel evidence that supports the therapeutic potential of berberine to combat vascular diseases. The purpose of this review is to comprehensively and systematically describe the evidence for berberine as a therapeutic agent in vascular diseases, including its pharmacological effects, molecular mechanisms, and pharmacokinetics. According to data published so far, berberine shows remarkable anti-inflammatory, antioxidant, antiapoptotic, and antiautophagic activity via the regulation of multiple signaling pathways, including AMP-activated protein kinase (AMPK), nuclear factor κB (NF-κB), mitogen-activated protein kinase silent information regulator 1 (SIRT-1), hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), janus kinase 2 (JAK-2), Ca2+ channels, and endoplasmic reticulum stress. Moreover, we discuss the existing limitations of berberine in the treatment of vascular diseases, and give corresponding measures. In addition, we propose some research perspectives and challenges, and provide a solid evidence base from which further studies can excavate novel effective drugs from Chinese medicine monomers.

Phosphodiesterase-1 inhibitor modulates Ca2+ regulation in sirtuin 1-deficient mouse cardiomyocytes.

BACKGROUND: Phosphodiesterase inhibitors can be used to enhance second messenger signaling to regulate intracellular Ca2+ cycling. This study investigated whether ITI-214, a selective phosphodiesterase-1 inhibitor, modulates intracellular Ca2+ regulation, resulting in a positive inotropic effect in sirtuin 1 (Sirt1)-deficient cardiomyocytes. METHODS: Mice with cardiac-specific Sirt1 knockout (Sirt1-/-) were used, with Sirt1flox/flox mice serving as controls. Electromechanical analyses of ventricular tissues were conducted, and we monitored intracellular Ca2+ using Fluo-3 as well as reactive oxygen species production in isolated cardiomyocytes. RESULTS: Sirt1-/- ventricles showed prolonged action potential duration at 90% repolarization and increased contractile force after treatment with ITI-214. The rates and sustained durations of burst firing in ventricles were higher and longer, respectively, in Sirt1-/- ventricles than in controls. ITI-214 treatment decreased the rates and shortened the durations of burst firing in Sirt1-/- mice. Sirt1-/- cardiomyocytes showed reduced Ca2+ transient amplitudes and sarcoplasmic reticulum (SR) Ca2+ stores compared to those in control cardiac myocytes, which was reversed after ITI-214 treatment. SR Ca2+ leakage was larger in Sirt1-/- cardiac myocytes than in control myocytes. ITI-214 reduced SR Ca2+ leakage in Sirt1-/- cardiac myocytes. Increased levels of reactive oxygen species in Sirt1-/- cardiomyocytes compared to those in controls were reduced after ITI-214 treatment. Levels of Ca2+ regulatory proteins, including ryanodine receptor 2, phospholamban, and sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a were not affected by ITI-214 administration. CONCLUSIONS: Our results suggest that ITI-214 improves intracellular Ca2+ regulation, which in turn exerts inotropic effects and suppresses arrhythmic events in Sirt1-deficient ventricular myocytes.

Mangosteen pericarp components alleviate progression of prostatic hyperplasia and mitochondrial dysfunction in rats.

Prostatic hyperplasia, characterized by progressive hyperplasia of glandular and stromal tissues, is the most common proliferative abnormality of the prostate in aging men. A high-fat diet (HFD) usually is a major factor inducing oxidative stress, inflammation, and an abnormal state of the prostate. Mangosteen pericarp powder (MPP) has abundant xanthones which can be antioxidant, anti-inflammatory, and antiproliferative agents. Therefore, the purpose of this study was to research whether MPP supplementation can affect the progression of prostatic hyperplasia. Twenty-four male F344 rats were randomly divided into four groups, including a control group (C), prostatic hyperplasia-induced group (P), prostatic hyperplasia-induced with low-dose MPP group (PL), and induced with high-dose MPP group (PH). The P, PL, and PH groups were given weekly intraperitoneal injections of 3,2'-dimethyl-4-aminobiphenyl (DMAB) at 25 mg/kg body weight for 10 weeks, and simultaneously fed an HFD for 24 weeks. Our findings first demonstrated that MPP consumption significantly decreased the prostate weight, serum testosterone and dihydrotestosterone concentrations, protein expression of proliferating cell nuclear antigen, and malondialdehyde levels and ameliorated mitochondrial function in prostatic tissues. These results suggest that MPP supplementation could be used to attenuate the progression of prostatic hyperplasia.

A review of traditional Chinese medicine on treatment of diabetic retinopathy and involved mechanisms.

As a common ocular complication and microangiopathy of type 2 diabetic mellitus, diabetic retinopathy (DR) can lead to vision loss or even blindness in diabetic patients. At present, the treatment methods of DR mainly include laser and anti-VEGF therapies. Nevertheless, the higher cost and obvious side effects seriously disturb the normal life of DR patients. Promisingly, traditional Chinese medicine (TCM) has been demonstrated to be effective in treating DR by tonifying Qi and nourishing Yin, as well clearing heat and breeding body fluids, thus activating blood and removing blood stasis. Therefore, we screened the literatures on TCM treatment of DR through the web of science, ScienceDirect, PubMed, Google scholar and CNKI online databases. The representative prescriptions, herbs and extracts, and identified compounds for treatment of DR were further summarized and analyzed. Moreover, the detailed mechanisms and involved network pathways of herbs-compounds-targets were visualized by Cytoscape software. Meanwhile, we discussed the existing limitations and deficiencies of TCM on treatment of DR and gave corresponding measures. In conclusion, TCM could significantly ameliorate DR via anti-inflammation, anti-oxidative stress, anti-angiogenesis and anti-apoptosis.