NIR-IIb fluorescence antiangiogenesis copper nano-reaper for enhanced synergistic cancer therapy.

The formation of blood vessel system under a relatively higher Cu2+ ion level is an indispensable precondition for tumor proliferation and migration, which was assisted in forming the tumor immune microenvironment. Herein, a copper ions nano-reaper (LMDFP) is rationally designed not only for chelating copper ions in tumors, but also for combination with photothermal therapy (PTT) to improve antitumor efficiency. Under 808 nm laser irradiation, the fabricated nano-reaper converts light energy into thermal energy to kill tumor cells and promotes the release of D-penicillamine (DPA) in LMDFP. Photothermal properties of LMDFP can cause tumor ablation in situ, which further induces immunogenic cell death (ICD) to promote systematic antitumor immunity. The released DPA exerts an anti-angiogenesis effect on the tumor through chelating copper ions, and inhibits the expression of programmed death ligand 1 (PD-L1), which synergizes with PTT to enhance antitumor immunity and inhibit tumor metastasis. Meanwhile, the nanoplatform can emit near-infrared-IIb (NIR-IIb) fluorescence under 980 nm excitation, which can be used to track the nano-reaper and determine the optimal time point for PTT. Thus, the fabricated nano-reaper shows powerful potential in inhibiting tumor growth and metastasis, and holds great promise for the application of copper nanochelator in precise tumor treatment.

Integrated Information for Pathogenicity and Treatment of Spiroplasma.

Spiroplasma, belonging to the class Mollicutes, is a small, helical, motile bacterium lacking a cell wall. Its host range includes insects, plants, and aquatic crustaceans. Recently, a few human cases of Spiroplasma infection have been reported. The diseases caused by Spiroplasma have brought about serious economic losses and hindered the healthy development of agriculture. The pathogenesis of Spiroplasma involves the ability to adhere, such as through the terminal structure of Spiroplasma, colonization, and invasive enzymes. However, the exact pathogenic mechanism of Spiroplasma remains a mystery. Therefore, we systematically summarize all the information about Spiroplasma in this review article. This provides a reference for future studies on virulence factors and treatment strategies of Spiroplasma.

NIR-II Fluorescence Imaging-Guided Oxygen Self-Sufficient Nano-Platform for Precise Enhanced Photodynamic Therapy.

Tumor hypoxia and systemic toxicity seriously affect the efficacy of photodynamic therapy (PDT) and are considered as the "Achilles' heel" of PDT. Herein, to combat such limitations, an intelligent orthogonal emissions LDNP@SiO2 -CaO2 and folic acid-polyethylene glycol-Ce6 nanodrug is rationally designed and fabricated not only for relieving the hypoxic tumor microenvironment (TME) to enhance PDT efficacy, but also for determining the optimal triggering time through second near-infrared (NIR-II) fluorescence imaging. The designed nanodrug continuously releases a large amount of O2 , H2 O2 , and Ca2+ ions when exposed to the acidic TME. Meanwhile, under downshifting NIR-II bioimaging guidance, chlorine e6 (Ce6) consumes oxygen to produce 1 O2 upon excitation of upconversion photon. Moreover, cytotoxic reactive oxygen species (ROS) and calcium overload can induce mitochondria injury and thus enhance the oxidative stress in tumor cells. As a result, the NIR-II bioimaging guided TME-responsive oxygen self-sufficient PDT nanosystem presents enhanced anti-tumor efficacy without obvious systemic toxicity. Thus, the fabricated nanodrug offers great potential for designing an accurate cancer theranostic system.

Curcumin attenuates inflammation of Macrophage-derived foam cells treated with Poly-L-lactic acid degradation via PPARγ signaling pathway.

Poly-L-lactic acid (PLLA) is considered to be a promising candidate material for biodegradable vascular scaffolds (BVS) in percutaneous coronary intervention (PCI). But, PLLA-BVS also faces the challenge of thrombosis (ST) and in-stent restenosis (ISR) caused by in-stent neo-atherosclerosis (ISNA) associated with inflammatory reactions in macrophage-derived foam cells. Our previous studies have confirmed that curcumin alleviates PLLA-induced injury and inflammation in vascular endothelial cells, but it remains unclear whether curcumin can alleviate the effect of inflammatory reactions in macrophage-derived foam cells while treated with degraded product of PLLA. In this study, PLLA-BVS was implanted in the porcine coronary artery to examine increased macrophages and inflammatory cytokines such as NF-κb and TNF-α by histology and immunohistochemistry. In vitro, macrophage-derived foam cells were induced by Ox-LDL and observed by Oil Red Staining. Foam cells were treated with pre-degraded PLLA powder, curcumin and PPARγ inhibitor GW9662, and the expression of IL-6, IL-10, TNF-α, NF-κb, PLA2 and PPARγ were investigated by ELISA or RT-qPCR. This study demonstrated that the macrophages and inflammatory factors increased after PLLA-BVS implantation in vivo, and foam cells derived from macrophages promoted inflammation by products of PLLA degradation in vitro. This present study was found that the inflammation of foam cells at the microenvironment of PLLA degraded products were significantly increased, and curcumin can attenuate the inflammation caused by the PLLA degradation via PPARγ signal pathway. In addition, curcumin should be further studied experimentally in vivo experiments on animal models as a potential therapeutic to reduce ISNA of PLLA-BVS. Graphical abstract.

A nanoselenium-coating biomimetic cytomembrane nanoplatform for mitochondrial targeted chemotherapy- and chemodynamic therapy through manganese and doxorubicin codelivery.

The cell membrane is widely considered as a promising delivery nanocarrier due to its excellent properties. In this study, self-assembled Pseudomonas geniculate cell membranes were prepared with high yield as drug nanocarriers, and named BMMPs. BMMPs showed excellent biosafety, and could be more efficiently internalized by cancer cells than traditional red cell membrane nanocarriers, indicating that BMMPs could deliver more drug into cancer cells. Subsequently, the BMMPs were coated with nanoselenium (Se), and subsequently loaded with Mn2+ ions and doxorubicin (DOX) to fabricate a functional nanoplatform (BMMP-Mn2+/Se/DOX). Notably, in this nanoplatform, Se nanoparticles activated superoxide dismutase-1 (SOD-1) expression and subsequently up-regulated downstream H2O2 levels. Next, the released Mn2+ ions catalyzed H2O2 to highly toxic hydroxyl radicals (·OH), inducing mitochondrial damage. In addition, the BMMP-Mn2+/Se nanoplatform inhibited glutathione peroxidase 4 (GPX4) expression and further accelerated intracellular reactive oxygen species (ROS) generation. Notably, the BMMP-Mn2+/Se/DOX nanoplatform exhibited increased effectiveness in inducing cancer cell death through mitochondrial and nuclear targeting dual-mode therapeutic pathways and showed negligible toxicity to normal organs. Therefore, this nanoplatform may represent a promising drug delivery system for achieving a safe, effective, and accurate cancer therapeutic plan.

Long-term clinical safety and efficacy of drug-coated balloon in the treatment of in-stent restenosis: A meta-analysis and systematic review.

OBJECTIVES: The aim of this study was to evaluate the long-term clinical safety and efficacy of drug-coated balloon (DCB) in the treatment of in-stent restenosis (ISR). BACKGROUND: There is a long-term safety issue in peripheral arterial disease patients treated with paclitaxel-coated balloon, this has also raised concerns on DCB in coronary intervention. METHODS: Nine randomized controlled trials (RCTs) and nine observational studies (OSs) were included with a total of 3,782 patients (1,827 in the DCB group, 1,955 in the drug-eluting stent [DES] group) being analyzed. The primary outcome measure-major adverse cardiovascular events (MACEs), target lesion revascularization (TLR), target vessel revascularization (TVR), myocardial infarction (MI), cardiac death (CD), stent thrombosis (ST), all-cause death (AD), and coronary angiography outcomes included late lumen loss (LLL), minimum luminal diameter (MLD), diameter stenosis (DS) were analyzed. RESULTS: DCB treatment significantly reduced the LLL (MD: -0.13; [CI -0.23 to -0.03], p = .01). No difference was found for MLD (MD: -0.1; [CI -0.24 to 0.04], p = .17) and DS% (RR = 0.98 [CI 0.80-1.20], p = .86). There was no significant difference in TLR, TVR, MI, CD, ST, AD, and the overall incidence of MACEs between the two groups up to 3 years follow-up. Subgroup analysis for different type of ISR and DES showed no significant difference in the incidence of endpoints, and there is no difference when considering RCTs or OSs only. CONCLUSIONS: The safety and efficacy of the DCB and DES in the treatment of ISR is comparable at up to 3 years follow-up.

Functional Analyses of a Novel CITED2 Nonsynonymous Mutation in Chinese Tibetan Patients with Congenital Heart Disease.

CITED2 gene is an important cardiac transcription factor that plays a fundamental role in the formation and development of embryonic cardiovascular. Previous studies have showed that knock-out of CITED2 in mice might result in various cardiac malformations. However, the mechanisms of CITED2 mutation on congenital heart disease (CHD) in Chinese Tibetan population are still poorly understood. In the present study, 187 unrelated Tibetan patients with CHD and 200 unrelated Tibetan healthy controls were screened for variants in the CITED2 gene; we subsequently identified one potential disease-causing mutation p.G143A in a 6-year-old girl with PDA and functional analyses of the mutation were carried out. Our study showed that the novel mutation of CITED2 significantly enhanced the expression activity of vascular endothelial growth factor (VEGF) under the role of co-receptor hypoxia inducible factor 1-aipha (HIF-1A), which is closely related with embryonic cardiac development. As a result, CITED2 gene mutation may play a significant role in the development of pediatric congenital heart disease.

Role of Cys³6°² in the function and regulation of the cardiac ryanodine receptor.

The cardiac Ca²âº release channel [ryanodine receptor type 2 (RyR2)] is modulated by thiol reactive agents, but the molecular basis of RyR2 modulation by thiol reagents is poorly understood. Cys³6³5 in the skeletal muscle RyR1 is one of the most hyper-reactive thiols and is important for the redox and calmodulin (CaM) regulation of the RyR1 channel. However, little is known about the role of the corresponding cysteine residue in RyR2 (Cys³6°²) in the function and regulation of the RyR2 channel. In the present study, we assessed the impact of mutating Cys³6°² (C³6°²A) on store overload-induced Ca²âº release (SOICR) and the regulation of RyR2 by thiol reagents and CaM. We found that the C³6°²A mutation suppressed SOICR by raising the activation threshold and delayed the termination of Ca²âº release by reducing the termination threshold. As a result, C³6°²A markedly increased the fractional Ca²âº release. Furthermore, the C³6°²A mutation diminished the inhibitory effect of N-ethylmaleimide on Ca²âº release, but it had no effect on the stimulatory action of 4,4'-dithiodipyridine (DTDP) on Ca²âº release. In addition, Cys³6°² mutations (C³6°²A or C³6°²R) did not abolish the effect of CaM on Ca²âº-release termination. Therefore, RyR2-Cys³6°² is a major site mediating the action of thiol alkylating agent N-ethylmaleimide, but not the action of the oxidant DTDP. Our data also indicate that residue Cys³6°² plays an important role in the activation and termination of Ca²âº release, but it is not essential for CaM regulation of RyR2.

A novel biosensor-based microarray assay for the visualized detection of CYP2C19 *2, *3, *4 and *5 polymorphisms.

BACKGROUND: A number of studies have indicated that the conversion of clopidogrel to its active metabolite is reduced in patients who carry the CYP2C19 *2, *3, *4 or *5 loss-of-function allele, resulting in decreased response of platelet to clopidogrel treatment and worse cardiovascular outcome. The aim of this study was to develop a novel biosensor-based microarray to visually detect CYP2C19 polymorphisms. METHODS: The target DNA was amplified from regions flanking the respective alleles using 5'-biotinylated reverse primer, and plasmids were prepared for the respective alleles. High stringency reversed hybridization, horseradish peroxidase-labeled streptavidin reaction, and color development, with multiple washes in different steps, were carried out and the results were recorded with an optical camera. The gene chips were tested for specificity, detection limit, intra- and inter-batch variations using the constructed plasmids. Finally, 88 clinical samples were assayed with this microarray as well as direct sequencing. RESULTS: The results could be seen with the naked eye. Concordance tests indicated that for alleles *2, *3, *4, and *5, the κ values between this assay and plasmids all reached 1.000. The detection limit was 5×10² cells/mL. Concordance test between direct sequencing and the microarray assay using 88 clinical samples gave rise to the κ value of 0.983, and p<0.01, indicating very high concordance. CONCLUSIONS: This novel biosensor-based microarray assay can amplify the signal in situ so that it can be detected by simple instruments or even the naked eyes. It is promising for clinical application in hospital laboratories.

A novel variation of GDF3 in Chinese Han children with a broad phenotypic spectrum of non-syndromic CHDs.

BACKGROUND: The GDF3 gene plays a fundamental role in embryonic morphogenesis. Recent studies have indicated that GDF3 plays a previously unrecognised role in cardiovascular system development. Non-syndromic CHDs might be a clinically isolated manifestation of GDF3 mutations. The purpose of the present study was to identify potential pathological mutations in the GDF3 gene in Chinese children with non-syndromic CHDs, and to gain insight into the aetiology of non-syndromic CHDs. METHODS: A total of 200 non-syndromic CHDs patients and 202 normal control patients were sampled. There were two exons of the human GDF3 gene amplified using polymerase chain reaction. The polymerase chain reaction products were purified and directly sequenced. RESULTS: One missense mutation (c.C635T, p.Ser212 Leu, phenotype: isolated muscular ventricular septal defect) was found that has not been reported previously. CONCLUSIONS: To the best of our knowledge, this is the first study to investigate the role of the GDF3 gene in non-syndromic CHDs. Our results expand the spectrum of mutations associated with CHDs and first suggest the potentially disease-related GDF3 gene variant in the pathogenesis of CHDs.

Novel fluorescent risedronates: synthesis, photodynamic inactivation and imaging of Bacillus subtilis.

Novel fluorescently-labeled conjugates of risedronate were synthesized using an epoxide linker, enabling conjugation of risedronate via its pyridyl nitrogen with the aromatic succinimidyl esters. The compounds were characterized by using (1)H NMR, (13)C NMR, (31)P NMR, UV-vis and fluorescence emission spectroscopies. Biological activity assays showed that the conjugates 14 and 15 exhibited photodynamic inactivation of Bacillus subtilis (ATCC 6633) with 91% and 47% bacterial lethality at 10 µM upon visible light irradiation, respectively. Both 14 and 15 could be also used for fluorescence imaging of Bacillus subtilis.

A novel fluorogenic substrate for dinuclear Zn(II)-containing metallo-ß-lactamases.

In an effort to prepare a fluorogenic substrate to be used in activity assays with metallo-ß-lactamases, (6R,7R)-8-oxo-7-(2-oxo-2H-chromene-3-carboxamido)-3-((4-(2-oxo-2H-chromene-3-carboxamido)-phenylthio)methyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (CA) was synthesized and characterized. CA exhibited a fluorescence quantum yield (φ) of 0.0059, two fluorescence lifetimes of 3.63×10(-10) and 5.38×10(-9)s, and fluorescence intensity that is concentration-dependent. Steady-state kinetic assays revealed that CA is a substrate for metallo-ß-lactamases (MßLs) L1 and CcrA, exhibiting Km and kcat values of 18µM and 5s(-1) and 11µM and 17s(-1), respectively.

Prevalence and Pattern of Congenital Heart Diseases in School Children in Dongguan, China.

BACKGROUND: To determine the prevalence and pattern of congenital heart disease (CHD) among elementary school children in Dongguan, China. METHODS: Between November 2011 and November 2012, 540,574 school children from 449 elementary schools were screened for CHD by trained doctors in Dongguan. The school children who were suspected to have CHD were referred to a pediatric cardiologist and/or an echocardiographer for a complete evaluation. RESULTS: The total prevalence of CHD was 2.14 per 1,000 school children (1,157/540,574). The most common form of CHD was isolated ventricular septal defect (37.77%; 437/1,157), followed by isolated atrial septal defect (20.22%; 234/1,157) and patent ductus arteriosus (9.94%; 115/1,157). With respect to sex, CHD was equally distributed between males and females. CONCLUSION: Our data show that the prevalence of CHD in Dongguan is not as high as expected and that isolated ventricular septal defect is the predominant pathology. Echocardiography plays a crucial role in the diagnosis of CHD.

Effect of Intensive Glycemic Control on Myocardial Infarction Outcome in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.

Background: The effect of intensive glucose-lowering treatment on the risk of cardiovascular events in type 2 diabetes remains uncertain, especially the effect on the occurrence of myocardial infarction in patients with type 2 diabetes is still unclear. The purpose of this study was to conduct a systematic review and meta-analysis of relevant RCTs. Methods: We performed a systematic review of randomized clinical trials (RCTS) and observational studies relevant to this study question. We searched the PubMed and Cochrane databases until June 2022. Results: We included data on 14 RCTs and 144,334 patients, all of whom had type 2 diabetes. When all studies were considered, intensive glucose-lowering treatment significantly reduced the incidence of MI compared with conventional therapy and the total OR value is 0.90 (CI 0.84, 0.97; P = 0.004) when considering all the studies. When the target value of intensive glucose-lowering treatment was considered as HbA1c decrease of more than 0.5%, there was no significant protective effect on MI, the total OR value is 0.88 (CI 0.81, 0.96; P = 0.003). When considering all available RCTS, the intensive glucose-lowering treatment group had a protective effect for MACE compared to the conventional treatment group, and the total OR value is 0.92 (CI 0.88, 0.96; P < 0.00001). In the available RCTs, for the patients with a history of prior CAD, the total OR value is 0.94 (CI 0.89, 0.99; P = 0.002). And there was no difference in the incidence of hypoglycemic events between the intensive and conservative treatment groups. Conclusion: Our data support the positive protective effect of glucose-lowering therapy on MI in patients with T2DM, but there is no significant effect of intensive glucose-lowering. In addition, we found no greater protective effect of enhanced glucose control in the HbA1c reduction of more than 0.5%, and no difference in the incidence of adverse events compared with the HbA1c reduction of less than 0.5%.

pH-Responsive Selenium Nanoplatform for Highly Efficient Cancer Starvation Therapy by Atorvastatin Delivery.

Recently, starvation-inducing nutrient deprivation has been regarded as a promising strategy for tumor suppression. As a first-line lipid-lowering drug, atorvastatin (ATV) significantly reduces caloric intake, suggesting its potential in starvation therapy for suppressing tumors. Accordingly, we developed a novel starvation therapy agent (HA-Se-ATV) in this study to suppress tumor growth by using hyaluronic acid (HA)-conjugated chitosan polymer-coated nano-selenium (Se) for loading ATV. HA-Se-ATV targets cancer cells, following which it effectively accumulates in the tumor tissue. The HA-Se-ATV nanoplatform was then activated by inducing a weakly acidic tumor microenvironment and subsequently releasing ATV. ATV and Se synergistically downregulate the levels of cellular adenosine triphosphate while inhibiting the expression of thioredoxin reductase 1. Consequently, the starvation-stress reaction of cancer cells is significantly elevated, leading to cancer cell death. Furthermore, the in vivo results indicate that HA-Se-ATV effectively suppresses tumor growth with a low level of toxicity, demonstrating its great potential for clinical translation.

Synthesis, characterization and activity of new phosphonate dipeptides as potential inhibitors of VanX.

VanX, a Zn(II)-dependent D-ala-D-ala dipeptidase, is essential for vancomycin resistance in Enterococcus faecium. The enzymatic activity of VanX was previously found to be inhibited competitively by 2-{[(1-aminoethyl) (hydroxy) phosphoryl]oxy} propanoic acid (1B). Here we report the synthesis and characterization of seven phosphonate dipeptide analogs of D-ala-D-ala with various substituent, the activity evaluation indicated that six of these phosphonate analogs inhibit VanX with IC(50) of 0.48-8.21mM. These data revealed a structure-activity relationship which is that the large substituent group on ß-carbon resulted in low binding affinity of the phonphonate analog to VanX. This information will be helpful to guide the design and synthesis of the tightly-binding inhibitors for VanX.

N-heterocyclic dicarboxylic acids: broad-spectrum inhibitors of metallo-ß-lactamases with co-antibacterial effect against antibiotic-resistant bacteria.

In an effort to identify novel, broad-spectrum inhibitors against the metallo-ß-lactamases (MßLs), several N-heterocyclic derivatives were tested as inhibitors of MßLs CcrA, ImiS, and L1, which are representative enzymes from the distinct MßL subclasses. Three N-heterocyclic dicarboxylic acid derivatives were competitive inhibitors of CcrA and L1, exhibiting K(i) values ≤2 µM, while only 2,4-thiazolidinedicarboxylic acid (1b) was a competitive inhibitor of ImiS. Two 2-mercapto-1,3,4-thiadiazole derivatives were noncompetitive inhibitors of CcrA and ImiS, exhibiting K(i) values <7 µM; however, these same compounds did not inhibit L1. Two 2-mercapto-1,3,4-triazole derivatives were shown not to inhibit any of the tested MßLs. The N-heterocyclic derivatives were tested for antibacterial activity by examining the MIC values for existing antibiotics in the presence/absence of these derivatives. Consistent with the steady-state inhibition data, the inclusion of three N-heterocyclic dicarboxylic acid derivatives resulted in lower MIC values when using Escherichia coli BL21(DE3) cells containing the CcrA or L1 plasmids or Klebsiella pneumoniae (ATCC 700603), while 1b was the only dicarboxylic acid derivative to lower the MIC value of E. coli cells containing the ImiS plasmid. Inclusion of the 2-mercapto-1,3,4-thiadiazole derivatives resulted in lower MIC values for E. coli cells containing ImiS or L1 plasmids; however, these derivatives did not alter the MIC values for K. pneumoniae or E. coli cells containing the L1 plasmid. None of the N-heterocyclic derivatives affected the MIC of two methicillin resistant Staphylococcus aureus (MRSA) strains. Taken together, these studies demonstrate that N-heterocyclic dicarboxylic acids 1a-c and pyridylmercaptothiadiazoles 2a,b are good scaffolds for future broad-spectrum inhibitors of the MßLs.

Effect of oxidative stress on ventricular arrhythmia in rabbits with adriamycin-induced cardiomyopathy.

The purpose of the present study was to examine the effects of oxidative stress on ventricular arrhythmias in rabbits with adriamycin-induced cardiomyopathy and the relationship between oxidative stress and ventricular arrhythmia. Forty Japanese white rabbits were randomly divided into four groups (n=10 in each): control group, metoprolol (a selective ß1 receptor blocker) group, carvedilol (a nonselective ß blocker/α-1 blocker) group and adriamycin group. Models of adriamycin-induced cardiomyopathy were established by intravenously injecting adriamycin hydrochloride (1 mg/kg) to rabbits via the auri-edge vein twice a week for 8 weeks in the adriamycin, metoprolol and carvedilol groups. Rabbits in the control group were given equal volume of saline through the auri-edge vein. Rabbits in the metoprolol and carvedilol groups were then intragastrically administrated metoprolol (5 mg/kg/d) and carvedilol (5 mg/kg/d) respectively for 2 months, while those in the adriamycin and control groups were treated with equal volume of saline in the same manner as in the metroprolol and carvedilol groups. Left ventricular end diastolic diameter (LVEDd) and left ventricular ejection fraction (LVEF) were measured by echocardiography. Plasma levels of N-terminal pro B-type natriuretic peptide (NT-proBNP), malondialdehyde (MAD) and superoxide dismutase (SOD) were detected. The left ventricular wedge preparations were perfused with Tyrode's solution. The transmural electrocardiogram, transmural action potentials from epicardium (Epi) and endocardium (Endo), transmural repolarization dispersion (TDR) were recorded, and the incidences of triggered activity and ventricular arrhythmias were obtained at rapid cycle lengths. The results showed that TDR and the serum MDA and NT-proBNP levels were increased, and LVEF and the serum SOD level decreased in the adriamycin group compared with the control group. The incidences of triggered activity and ventricular arrhythmia were significantly higher in the adriamycin group than those in the control group (P<0.05). In the carvedilol group as compared with the adriamycin group, the serum SOD level and the LVEF were substantially increased; the TDR, and the serum MDA and NT-proBNP levels were significantly decreased; the incidences of triggered activity and ventricular arrhythmia were obviously reduced (P<0.05). There were no significant differences in the levels of MDA and SOD, LVEF, TDR and the incidences of triggered activity and ventricular arrhythmia between the adriamycin group and the metoprolol group. It was concluded that carvedilol may inhibit triggered activity and ventricular arrhythmias in rabbit with adriamycin-induced cardiomyopathy, which is related to the decrease in oxygen free radials.

RNA Sequencing of Cardiac in a Rat Model Uncovers Potential Target LncRNA of Diabetic Cardiomyopathy.

Background: Diabetic cardiomyopathy (DCM) is one of the major causes of heart failure in diabetic patients; however, its pathogenesis remains unclear. Long non-coding RNAs (lncRNAs) are involved in the development of various cardiovascular diseases, but little is known in DCM. Objective: The present study was conducted to investigate the altered expression signature of lncRNAs and mRNAs by RNA-sequencing and uncovers the potential targets of DCM. Methods: A DCM rat model was established, and the genome-wide expression profile of cardiac lncRNAs and mRNAs was investigated in the rat model with and without DCM by RNA-sequencing. Bioinformatics analysis included the co-expression, competitive endogenous RNA (ceRNA) network, and functional enrichment analysis of deregulated lncRNAs and mRNAs. Results: A total of 355 lncRNA transcripts and 828 mRNA transcripts were aberrantly expressed. The ceRNA network showed that lncRNA XR_351927.3, ENSRNOT00000089581, XR_597359.2, XR_591602.2, and XR_001842089.1 are associated with the greatest number of differentially expressed mRNAs and AURKB, MELK, and CDK1 may be the potential regulatory targets of these lncRNAs. Functional analysis showed that these five lncRNAs are closely associated with fibration, cell proliferation, and energy metabolism of cardiac myocytes, indicating that these core lncRNAs have high significance in DCM. Conclusions: The present study profiled the DCM-specific lncRNAs and mRNAs, constructed the lncRNA-related ceRNA regulatory network, and identified the potential prognostic biomarkers, which provided new insights into the pathogenesis of DCM.

Multi-omics insights into potential mechanism of SGLT2 inhibitors cardiovascular benefit in diabetic cardiomyopathy.

Background: Metabolic and energy disorders are considered central to the etiology of diabetic cardiomyopathy (DCM). Sodium-glucose cotransporter-2 inhibitors (SGLT2i) can effectively reduce the risk of cardiovascular death and heart failure in patients with DCM. However, the underlying mechanism has not been elucidated. Methods: We established a DCM rat model followed by treatment with empagliflozin (EMPA) for 12 weeks. Echocardiography, blood tests, histopathology, and transmission electron microscopy (TEM) were used to evaluate the phenotypic characteristics of the rats. The proteomics and metabolomics of the myocardium in the rat model were performed to identify the potential targets and signaling pathways associated with the cardiovascular benefit of SGLT2i. Results: The diabetic rat showed pronounced DCM characterized by mitochondrial pleomorphic, impaired lipid metabolism, myocardial fibrosis, and associated diastolic and systolic functional impairments in the heart. To some extent, these changes were ameliorated after treatment with EMPA. A total of 43 proteins and 34 metabolites were identified as targets in the myocardium of diabetic rats treated with EMPA. The KEGG analysis showed that arachidonic acid is associated with the maximum number of related pathways and may be a potential target of EMPA treatment. Fatty acid (FA) metabolism was enhanced in diabetic hearts, and the perturbation of biosynthesis of unsaturated FAs and arachidonic acid metabolism was a potential enabler for the cardiovascular benefit of EMPA. Conclusion: SGLT2i ameliorated lipid accumulation and mitochondrial damage in the myocardium of diabetic rats. The metabolomic and proteomic data revealed the potential targets and signaling pathways associated with the cardiovascular benefit of SGLT2i, which provides a valuable resource for the mechanism of SGLT2i.