Métodos diagnósticos cardiovasculares en pacientes con diabetes mellitus. Revisión / Cardiovascular diagnostic methods in patients with diabetes mellitus. A review

Resumen Las enfermedades cardiovasculares constituyen la causa más común de mortalidad en el mundo. Actualmente, la diabetes mellitus tipo 2 (DM2) representa uno de los principales factores de riesgo de eventos adversos cardiovasculares mayores. Los pacientes que las padecen tienen un riesgo cuatro veces mayor de desarrollar insuficiencia cardíaca y una mortalidad de 10 a 12 veces mayor. La ecocardiografía en todas sus modalidades es la mejor herramienta clínica para el diagnóstico de la insuficiencia cardíaca, ya que proporciona imágenes estáticas y dinámicas del corazón que permiten identificar cambios estructurales y funcionales, como alteraciones en las presiones, cambios de flujo, fracción de expulsión del ventrículo izquierdo y remodelación anatómica de las superficies miocárdicas.

Abstract Cardiovascular diseases are the most common cause of mortality in the world. Currently, type 2 diabetes mellitus (T2DM) is one of the main risk factors for major adverse cardiovascular events. T2DM patients have a four-fold higher risk of developing heart failure and 10 to 12 times higher mortality. Echocardiography in all its modalities is the best clinical tool for heart failure diagnosis, since it provides static and dynamic images of the heart that allow to identify structural and functional changes, such as pressure variations, flow changes, left ventricular ejection fraction and myocardial surfaces anatomical remodeling.

Mecanismos y dianas terapéuticas del inflamasoma NLRP3 en la miocardiopatía diabética / NLRP3 inflammasome mechanism and therapeutic targets in diabetic cardiomyopathy

Resumen La cardiomiopatía diabética es una complicación grave de la diabetes causada por estrés oxidativo, inflamación, resistencia a la insulina, fibrosis miocárdica y lipotoxicidad. Se trata de un padecimiento insidioso, complejo y difícil de tratar. El inflamasoma NLRP3 desencadena la maduración y liberación de citoquinas proinflamatorias, participa en procesos fisiopatológicos como la resistencia a la insulina y la fibrosis miocárdica, además de estar estrechamente relacionado con la aparición y progresión de la cardiomiopatía diabética. El desarrollo de inhibidores dirigidos a aspectos específicos de la inflamación sugiere que el inflamasoma NLRP3 puede utilizarse para tratar la cardiomiopatía diabética. Este artículo pretende resumir el mecanismo y las dianas terapéuticas del inflamasoma NLRP3 en la cardiomiopatía diabética, así como aportar nuevas sugerencias para el tratamiento de esta enfermedad.

Abstract Diabetic cardiomyopathy (DCM) is a serious complication of diabetes caused by oxidative stress, inflammation, insulin resistance, myocardial fibrosis, and lipotoxicity; its nature is insidious, complex and difficult to treat. NLRP3 inflammasome triggers the maturation and release of pro-inflammatory cytokines, participates in pathophysiological processes such as insulin resistance and myocardial fibrosis, in addition to being closely related to the development and progression of diabetic cardiomyopathy. The development of inhibitors targeting specific aspects of inflammation suggests that NLRP3 inflammasome can be used to treat diabetic cardiomyopathy. This paper aims to summarize NLRP3 inflammasome mechanism and therapeutic targets in diabetic cardiomyopathy, and to provide new suggestions for the treatment of this disease.

Analysis of circRNA expression profile and functional enrichment of myocardial mitochondria in mice with diabetic cardiomyopathy / 西安交通大学学报(医学版)

【Objective】 To explore the differential expression and functional analysis of circRNA from myocardial mitochondria in diabetes cardiomyopathy (DCM) mice. 【Methods】 The DCM mice model was established in 16-week-old db/db mice, and C57BL/KsJ mice were used as controls. RNA was extracted from the myocardium of two groups of mice, high-throughput sequencing was used to screen mitochondrial circRNA differentially expressed in the two groups, RT-qPCR was used to verify the sequencing results of the first 10 circRNAs with significant differential expression, and functional enrichment analysis was performed on the differentially expressed circRNA target genes, and miRNA target prediction software was used to analyze the circRNA-miRNA co-expression network. 【Results】 There were 147 mitochondrial circRNAs differentially expressed in the myocardium of DCM mice, including 89 highly expressed and 58 low expressed. The expression pattern of differentially expressed circRNAs in tissues was consistent with those of sequencing results. The enrichment analysis of GO and KEGG showed that the differentially expressed circRNA target genes were mainly enriched in cGMP/PKG, glucagon pathways, which were related to mitochondrial energy metabolism and cardiac hypertrophy. circRNA-miRNA co-expression analysis found that the most significantly up-regulated circRNA, chrM:1207-1536+, was associated with miR-491-3p, miR-99a-3p, and miR-99b-3p, and the most significantly down-regulated circRNA, chrM:1453-3205+, was associated with miR-181b-1-3p, miR-181b-2-3p, and miR-672-5p. 【Conclusion】 Compared to the control mice, there is differential expression of circRNAs in myocardial mitochondria of DCM mice. The differentially expressed circRNAs may interact with the corresponding miRNA to affect myocardial fibrosis and hypertrophy through regulation of energy metabolism, apoptosis and other pathways, thus participating in the pathogenesis of DCM.

Chinese Medicine Intervention in Diabetic Cardiomyopathy Based on Autophagy：A Review / 中国实验方剂学杂志

Autophagy is a lysosome-dependent intracellular degradation process，and it is a key mechanism of diabetic cardiomyopathy （DCM）. Autophagy has dual regulatory effects on DCM. Under physiological conditions，normal autophagy can promote the decomposition of damaged cardiomyocytes and metabolites，so as to reduce the damage of harmful substances to the body and provide energy for cardiomyocytes. Under pathological conditions，the inhibited autophagy of cardiomyocytes will cause the accumulation of damaged cells and metabolites，which will cause damage to cardiomyocytes and eventually aggravate cardiac dysfunction in the patients with DCM. However，the over autophagy of cardiomyocytes will lead to autophagic death of a large number of cardiomyocytes and result in pathological myocardial remodeling and cardiac dysfunction，thus promoting the progression of DCM. Therefore，the restoration of a normal autophagy level is the key means to protect cardiomyocytes and improve the prognosis of DCM. Chinese medicine can regulate autophagy to treat DCM. Specifically，it can promote autophagy （making up for deficiency） or inhibit autophagy （removing excess） to restore the balance of autophagy，thereby alleviating DCM.

Advance of mitophagy in diabetic cardiomyopathy / 中华内分泌代谢杂志

Diabetic cardiomyopathy is a myocardial complication associated with abnormal glucose metabolism and dyslipidiaemia, which increases the risk of death and heart failure in diabetic patients. Mitochondrial dysfunction is involved in the occurrence and development of diabetic cardiomyopathy. Recent studies have confirmed that scavenging damaged mitochondria in cardiomyocytes through mitophagy can restore mitochondrial homeostasis, reduce oxidative stress and improve diabetic cardiomyopathy. Therefore, this article provides a comprehensive review of the mechanisms and characteristics of mitochondrial autophagy in diabetic cardiomyopathy. It aims to offer new insights and theoretical basis for the prevention and treatment of diabetic cardiomyopathy.

Relationship Between NLRP3 Inflammasome and Diabetic Cardiomyopathy and Intervention Effect of Traditional Chinese Medicine： A Review / 中国实验方剂学杂志

Diabetic cardiomyopathy （DCM） is one of the complications of diabetes. It refers to a specific type of idiopathic cardiomyopathy that occurs in individuals with diabetes， distinct from other cardiovascular diseases such as coronary heart disease， valvular heart disease， or congenital heart disease. It has also been identified as one of the leading causes of death in diabetic patients for many years. Research has shown that the pathogenesis of DCM is closely associated with insulin resistance， activation of various inflammatory responses， increased oxidative stress， impaired coronary microcirculation， and accumulation of advanced glycation end products （AGEs）. Among various inflammatory responses， the activation of the NOD-like receptor protein 3 （NLRP3） inflammasome can induce the secretion of a large amount of pro-inflammatory cytokines through the cascade reaction of inflammation， subsequently mediating cellular pyroptosis and promoting myocardial damage. Currently， extensive experimental studies on traditional Chinese medicine （TCM） have been conducted in China and abroad based on the significant role of the NLRP3 inflammasome in the prevention and treatment of DCM. These studies have demonstrated that Chinese medicinal extracts， such as Astragalus polysaccharide and ginsenoside Rb1， single drugs like Coriolus and Cordyceps， and Chinese medicinal formulas like Didangtang and modified Taohe Chengqitang， as well as acupuncture and TCM exercise therapy， can regulate the relevant pathways of the NLRP3 inflammasome to inhibit its assembly or activation， reduce inflammatory responses， inhibit myocardial remodeling in DCM， and improve cardiac function. This article reviewed the relationship between the NLRP3 inflammasome and DCM， as well as the research progress on TCM in exerting anti-inflammatory effects in this field， aiming to provide new insights for the development of therapeutic approaches for DCM.

Effects of Angelica sinensis polysaccharide on the apoptosis of cardiomyocytes in diabetic KK-Ay mice / 中国药房

OBJECTIVE To investigate the effects of Angelica sinensis polysaccharide on the apoptosis of cardiomyocytes in diabetic KK-Ay mice. METHODS KK-Ay mice were randomly divided into model group， metformin group （200 mg/kg） and A. sinensis polysaccharide high-dose， medium-dose and low-dose groups （400， 200 and 100 mg/kg）； C57BL/6J mice were included in blank group， with 8 mice in each group. Each group was given relevant medicine intragastrically or normal saline， once a day， for consecutive 4 weeks. After the final administration， the levels of fasting glucose， total cholesterol （TC）， low-density lipoprotein cholesterol （LDL-C） and insulin （INS） were detected； the protein expressions of B-cell lymphoma 2 （Bcl-2）， cleaved- caspase-3， apoptosis signal-regulated kinase 1 （ASK1）， phosphorylated c-Jun N-terminal kinase （p-JNK）， phosphorylated inositol- requiring enzyme 1α （p-IRE1α） in myocardium， and apoptosis in cardiomyocytes were also detected. RESULTS Compared with model group， the fasting glucose， TC and LDL-C content， apoptotic rate of cardiomyocyte， protein expressions of p-JNK and p- IRE1α， ASK1， cleaved-caspase-3 were significantly lower in the metformin group and A. sinensis polysaccharide medium-dose， high-dose groups； INS level and relative expression of Bcl-2 protein were significantly increased （P＜0.05 or P＜0.01）. CONCLUSIONS A. sinensis polysaccharide can improve the levels of blood glucose and blood lipid and inhibit cardiomyocyte apoptosis in diabetic KK-Ay mice， and the mechanism may be related to the inhibition of IRE1/ASK1/JNK signaling pathway.

A systematic review of preclinical animal studies on fenofibrate's potential role in type 1 diabetic micro-vascular complications

Abstract Fenofibrate is a peroxisome-proliferator-activator α agonist and it is a widely used drug for hyperlipidemia since its approval in 2004. So, in this review we are focusing on the effect of fenofibric acid's mechanism to alleviate type 1 diabetic micro vascular complications like diabetic retinopathy, diabetic cardiomyopathy in animal models, since the drug is safe, efficacious and more economical when compared with the currently available treatment strategies for juvenile diabetic complications and also a profound observation is needed due to the rarity of research in these therapeutic areas. Important preclinical animal studies published from January 2001 to June 2020 were recognised from databases like PubMed and Cochrane central register of controlled trials. Reviewers screened the articles based on the selection criteria and risk of bias was determined using Systematic Review Centre for Laboratory animal Experimentation risk of bias tool for animal studies. Our literature search yielded a total of 5 studies and after pooling up the data from the 5 preclinical studies, we found that Fenofibrate have the efficacy to prevent type 1 diabetic complications, chiefly diabetic retinopathy and those mechanisms are dependent on peroxisome-proliferator-activator and fibroblast growth factor-21 pathways. Fenofibrate is a well safe and moreover, cost effective medication in preventing type 1 diabetic micro vascular complications especially diabetic retinopathy and also in maintaining the glucose homeostasis in apart from its anti-dyslipidemic effect.

Hyperglycemic memory in diabetic cardiomyopathy / 医学前沿

Cardiovascular diseases account for approximately 80% of deaths among individuals with diabetes mellitus, with diabetic cardiomyopathy as the major diabetic cardiovascular complication. Hyperglycemia is a symptom that abnormally activates multiple downstream pathways and contributes to cardiac hypertrophy, fibrosis, apoptosis, and other pathophysiological changes. Although glycemic control has long been at the center of diabetes therapy, multicenter randomized clinical studies have revealed that intensive glycemic control fails to reduce heart failure-associated hospitalization and mortality in patients with diabetes. This finding indicates that hyperglycemic stress persists in the cardiovascular system of patients with diabetes even if blood glucose level is tightly controlled to the normal level. This process is now referred to as hyperglycemic memory (HGM) phenomenon. We briefly reviewed herein the current advances that have been achieved in research on the underlying mechanisms of HGM in diabetic cardiomyopathy.

Ferroptosis is essential for diabetic cardiomyopathy and is prevented by sulforaphane via AMPK/NRF2 pathways

Herein, we define the role of ferroptosis in the pathogenesis of diabetic cardiomyopathy (DCM) by examining the expression of key regulators of ferroptosis in mice with DCM and a new ex vivo DCM model. Advanced glycation end-products (AGEs), an important pathogenic factor of DCM, were found to induce ferroptosis in engineered cardiac tissues (ECTs), as reflected through increased levels of Ptgs2 and lipid peroxides and decreased ferritin and SLC7A11 levels. Typical morphological changes of ferroptosis in cardiomyocytes were observed using transmission electron microscopy. Inhibition of ferroptosis with ferrostatin-1 and deferoxamine prevented AGE-induced ECT remodeling and dysfunction. Ferroptosis was also evidenced in the heart of type 2 diabetic mice with DCM. Inhibition of ferroptosis by liproxstatin-1 prevented the development of diastolic dysfunction at 3 months after the onset of diabetes. Nuclear factor erythroid 2-related factor 2 (NRF2) activated by sulforaphane inhibited cardiac cell ferroptosis in both AGE-treated ECTs and hearts of DCM mice by upregulating ferritin and SLC7A11 levels. The protective effect of sulforaphane on ferroptosis was AMP-activated protein kinase (AMPK)-dependent. These findings suggest that ferroptosis plays an essential role in the pathogenesis of DCM; sulforaphane prevents ferroptosis and associated pathogenesis via AMPK-mediated NRF2 activation. This suggests a feasible therapeutic approach with sulforaphane to clinically prevent ferroptosis and DCM.

Preliminary evidence for the presence of multiple forms of cell death in diabetes cardiomyopathy

Diabetic mellitus (DM) is a common degenerative chronic metabolic disease often accompanied by severe cardiovascular complications (DCCs) as major causes of death in diabetic patients with diabetic cardiomyopathy (DCM) as the most common DCC. The metabolic disturbance in DCM generates the conditions/substrates and inducers/triggers and activates the signaling molecules and death executioners leading to cardiomyocyte death which accelerates the development of DCM and the degeneration of DCM to heart failure. Various forms of programmed active cell death including apoptosis, pyroptosis, autophagic cell death, autosis, necroptosis, ferroptosis and entosis have been identified and characterized in many types of cardiac disease. Evidence has also been obtained for the presence of multiple forms of cell death in DCM. Most importantly, published animal experiments have demonstrated that suppression of cardiomyocyte death of any forms yields tremendous protective effects on DCM. Herein, we provide the most updated data on the subject of cell death in DCM, critical analysis of published results focusing on the pathophysiological roles of cell death, and pertinent perspectives of future studies.

Effect of Modified Taohe Chengqitang on NLRP3 Inflammasomes in Rats with Diabetic Cardiomyopathy / 中国实验方剂学杂志

ObjectiveTo investigate the effect of modified Taohe Chengqitang on NOD-like receptor protein 3 （NLRP3） inflammasome activation in rats with diabetic cardiomyopathy. MethodSPF male SD rats aged 3-4 weeks were randomly divided into a normal group and an experimental group. The rats in the experimental group were fed on a high-fat diet for 4 weeks and then received intraperitoneal injection of streptozotocin （STZ） at 35 mg·kg-1 to induce the diabetes model. The rats in the experimental group were randomly divided into model group， low- and high-dose modified Taohe Chengqitang groups （11.7 g·kg-1 and 23.4 g·kg-1）， and metformin hydrochloride group （67.5 mg·kg-1） according to the fast blood glucose （FBG）. The cardiac function and structure of rats were detected by ultrasonic imaging after 8 weeks of continuous intragastric administration. Blood samples from the femoral artery were collected to detect FBG， triglyceride （TC）， and total cholesterol （TG） of rats. Hematoxylin-eosin （HE） staining was used to observe the pathological changes in rat myocardium. Serum levels of interleukin-1β （IL-1β） and interleukin-18 （IL-18） were determined by enzyme-linked immunosorbent assay （ELISA）. The protein expression of NLRP3， apoptosis-associated speck-like protein containing a CARD （ASC）， cysteinyl aspartate-specific protease 1 （Caspase-1）， and phosphorylated nuclear factor kappa-B p65 （p-NF-κB p65） in the myocardium was detected by Western blot. ResultCompared with the normal group， the model group showed increased levels of FBG， TC， and TG （P<0.01）， decreased left ventricular ejection fraction （EF） and left ventricular fractional shortening （FS） （P<0.05）， myocardial hypertrophy and myocardial fibrosis as revealed by HE staining， increased serum levels of 1L-1β and 1L-18 and protein expression of NLRP3， ASC， Caspase-1， and p-NF-κB p65 in myocardial tissues （P<0.01）. Compared with the model group， the modified Taohe Chengqitang groups and the metformin group showed reduced levels of FBG， TC， and TG （P<0.05）， restored EF and FS （P<0.05）， improved pathological changes in myocardial tissues， and decreased serum levels of IL-1β and IL-18 and protein expression of NLRP3， ASC， Caspase-1， and p-NF-κB p65 in myocardial tissues （P<0.05）. The improvement was more significant in the high-dose modified Taohe Chengqitang group （P<0.05）. ConclusionModified Taohe Chengqitang can protect the myocardium by inhibiting the activation of NLRP3 inflammasomes.

Action Mechanism of Chinese Medicine Polysaccharides in Prevention and Treatment Diabetes and Its Complications：A Review / 中国实验方剂学杂志

Diabetes is a metabolic disease mainly characterized by hyperglycemia due to inadequate insulin secretion. And persistent hyperglycemia can cause chronic damage or dysfunction of eyes， kidneys， heart， blood vessels and nerves. Polysaccharides are high molecular carbohydrates polymerized by glycosidic bonds from more than 10 monosaccharide molecules of the same or different types. They have the advantages of wide sources， high safety and low toxic and so on. As one of the important effective components of traditional Chinese medicine， polysaccharides have biological activities such as immune regulation， anti-oxidation， anti-tumor， lowering blood sugar and so on. The structure is directly related to biological activities， and the advanced structure of polysaccharides is based on the primary structure. Exploring the primary structure of polysaccharides is the key task of lowering blood sugar and improving diabetic complications. This paper summarizes the monosaccharide composition of the primary structure of Chinese medicine polysaccharides， and the mechanism of Chinese medicine polysaccharides improving diabetes is emphasized by increasing the secretion and release of insulin， increasing the islet β cell number， upregulating insulin receptor level， improving glucose and lipid metabolism， inhibiting inflammatory response， improving oxidative stress and regulating phosphatidylinositol-3-kinase（PI3K）/protein kinase B （Akt）， mitogen activated protein kinase， cyclic adenosine monophosphate（cAMP）/protein kinase A（PKA） and adenosine monophosphate activated protein kinase（AMPK） signaling pathways. At the same time， we also summarized the prevention and treatment of Chinese medicine polysaccharides in diabetic nephropathy， diabetic cardiomyopathy， diabetic ophthalmopathy and diabetic peripheral neuropathy， in order to provide a theoretical basis for new drug development and clinical application of Chinese medicine polysaccharides in the intervention of diabetes and its complications.

Pathogenesis and Drug Intervention of Diabetic Cardiomyopathy： A Review / 中国实验方剂学杂志

Diabetic cardiomyopathy， one of the cardiovascular complications of diabetes， is characterized by cardiac systolic and diastolic dysfunction at the early stage， which can later develop into heart failure. Due to the high incidence and mortality， it has been a hot topic in recent years. The pathogenesis of diabetic cardiomyopathy is complicated. It has been proved related to abnormal glucose and lipid metabolism， cardiac insulin resistance， mitochondrial dysfunction， abnormal calcium homeostasis， activation of renin-angiotensin-aldosterone system， increased oxidative stress， endoplasmic reticulum stress， inflammation， autophagy， and so on. The specific pathogenesis remains unclear. Currently， the diabetic cardiomyopathy is mainly tackled with both western medicine and traditional Chinese medicine （TCM）. Traditional western medicine has no specific remedy for diabetic cardiomyopathy， and the resulting side effect cannot be neglected. In order to improve the efficacy and reduce the side effects， researchers have tried some potential medical treatments， such as vaspin， melatonin， Coenzyme Q10， and non-coding RNA， which still need further clinical trials. Diabetic cardiomyopathy is not recorded in ancient TCM books. According to the symptoms and signs， modern physicians often consider it as a "consumptive disease"， whose main therapeutic principles lie in benefiting Qi， tonifying Yin， activating blood， and removing stasis. The individual Chinese herbs such as Astragali Radix and Salviae Miltiorrhizae Radix et Rhizoma and Chinese herbal compounds like Huotan Jiedu Tongluoyin are effective in protecting the heart. But there are few studies exploring the pharmacodynamic mechanisms of TCM. With the continuous emergence of new drugs， the integration of TCM with western medicine may be a more promising treatment in the future. In conclusion， the pathogenesis of diabetic cardiomyopathy is unclear， and there is a lack of effective prevention and treatment. This paper reviewed the latest findings in pathogenesis and treatment of diabetic cardiomyopathy， in order to provide reference for further research.

Effect of Didang Xianxiong Decoction on Cardiac Myocardial Microvascular Endothelial Cell Injury Induced by High Glucose / 中国实验方剂学杂志

ObjectiveThis study was designed to observe the effect of Didang Xianxiong decoction on the cardiac myocardial microvascular endothelial cells （CMECs） injury， and to explore its related mechanism based on the CMECs model induced by high glucose. MethodRat primary myocardial cells were cultured in vitro and 33 mmol·L-1 glucose was added for modeling. After modeling， the rats were randomly divided into model group （final glucose concentration： 33 mmol·L-1）， normal group， Didang Xianxiong decoction low dose group （glucose + 5% Didang Xianxiong decoction containing serum）， Didang Xianxiong decoction medium dose group （glucose+10% Didang Xianxiong decoction containing serum）， Didang Xianxiong decoction high dose group （glucose+20% Didang Xianxiong decoction containing serum） and alagebrium chloride （ALT-711） group （glucose+10% ALT-711 containing serum）. The influence of drug-containing serum on the proliferation of CMECs was detected by MTT tetrazolium salt colorimetric assay. The relative mRNA expression of c-Jun was detected by real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）. The protein expression of phosphorylated Janus kinase 1 （p-JAK1）， phosphorylated signal transducer and activator of transcription 1 （p-STAT1） and transforming growth factor-β1 （TGF-β1） was determined by Western blot. ResultCompared with the conditions in normal group， the mRNA expression of c-Jun and protein expression of p-JAK1， p-STAT1 and TGF-β1 were up-regulated in model group （P<0.01）. Compared with model group， all treatment groups had decreased mRNA expression of c-Jun （P<0.01）. Didang Xianxiong decoction medium and high dose groups and ALT-711 group showed reduced protein expression of p-JAK1 and p-STAT1 （P<0.05， P<0.01）， while there was no significant change in Didang Xianxiong decoction low dose group. TGF-β1 protein expression was lowered in all treatment groups （P<0.05， P<0.01）， and the decrease was more significant in Didang Xianxiong decoction medium and high dose groups than Didang Xianxiong decoction low dose group. ConclusionDidang Xianxiong decoction can protect CMECs with high glucose-induced injury， and the mechanism may be related to reducing the activity of JAK/STAT signaling pathway in cells.

Fucoxanthin regulates Nrf2/Keap1 signaling to alleviate myocardial hypertrophy in diabetic rats / 南方医科大学学报

OBJECTIVE@#To investigate the protective effect of fucoxanthin (FX) against diabetic cardiomyopathy and explore the underlying mechanism.@*METHODS@#Rat models of diabetes mellitus (DM) induced by intraperitoneal injection of streptozotocin (60 mg/kg) were randomized into DM model group, fucoxanthin treatment (DM+FX) group and metformin treatment (DM+ Met) group, and normal rats with normal feeding served as the control group. In the two treatment groups, fucoxanthin and metformin were administered after modeling by gavage at the daily dose of 200 mg/kg and 230 mg/kg, respectively for 12 weeks, and the rats in the DM model group were given saline only. HE staining was used to examine the area of cardiac myocyte hypertrophy in each group. The expression levels of fibrotic proteins TGF-β1 and FN proteins in rat hearts were detected with Western blotting. In the cell experiment, the effect of 1 μmol/L FX on H9C2 cell hypertrophy induced by exposure to high glucose (HG, 45 mmol/L) was evaluated using FITC-labeled phalloidin. The mRNA expression levels of the hypertrophic factors ANP, BNP and β-MHC in H9C2 cells were detected using qRT-PCR. The protein expressions of Nrf2, Keap1, HO-1 and SOD1 proteins in rat heart tissues and H9C2 cells were determined using Western blotting. The DCFH-DA probe was used to detect the intracellular production of reactive oxygen species (ROS).@*RESULTS@#In the diabetic rats, fucoxanthin treatment obviously alleviated cardiomyocyte hypertrophy and myocardial fibrosis, increased the protein expressions of Nrf2 and HO-1, and decreased the protein expressions of Keap1 in the heart tissue (P < 0.05). In H9C2 cells with HG exposure, fucoxanthin significantly inhibited the enlargement of cell surface area, lowered the mRNA expression levels of ANP, BNP and β-MHC (P < 0.05), promoted Nrf2 translocation from the cytoplasm to the nucleus, and up-regulated the protein expressions its downstream targets SOD1 and HO-1 (P < 0.05) to enhance cellular antioxidant capacity and reduce intracellular ROS production.@*CONCLUSION@#Fucoxanthin possesses strong inhibitory activities against diabetic cardiomyocyte hypertrophy and myocardial fibrosis and is capable of up-regulating Nrf2 signaling to promote the expression of its downstream antioxidant proteins SOD1 and HO-1 to reduce the level of ROS.

Inhibition of Toll-like Receptor-4 expression for amelioration of myocardial injury in diabetes: A meta-analysis

Abstract To understand the relationship between the inhibition of Toll-Like Receptor-4 (TLR4) expression levels and diabetic myocardial injury, studies on TLR4 and diabetic myocardial injury in the China National Knowledge Internet (CNKI), WanFang database, VIP Database, PubMed, The Cochrane Library, Web of Science, and other databases were explored (retrieval details: November 2020). A meta-analysis of the selected literature was performed using the RevMan 5.4 software to detect publication bias using funnel plots and conduct a sensitivity analysis. Nine publications were finally included in this study, of which six included data on Heart Weight/Body Weight (HW/BW) indexes, and five included data on Left Ventricular Systolic Pressure (LVSP) and Left Ventricular End-Diastolic Pressure (LVEDP) indices. The meta-analysis showed that HW/BW was significantly reduced after the suppression of TLR4 expression (Standardized Mean Difference [SMD = 1.9], 95% CI between 0.59 and 3.21, p = 0.004), LVSP was significantly improved (SMD = -2.39, 95% CI between -4.32 and -0.46, p = 0.02), and LVEDP was significantly reduced (SMD = 2.88, 95% CI between 1.05 and 4.71, p = 0.002). The TLR4 signaling pathway plays an essential role in the pathogenesis of Diabetic Cardiomyopathy (DCM). Inhibition of TLR4 expression can improve the degree of cardiac impairment. TLR4 may become a new target for the treatment of DCM, and the use of TLR4 inhibitors may prove to be a novel strategy for therapeutic research.

Stingless bee propolis, metformin, and their combination alleviate diabetic cardiomyopathy

Abstract Background and aim: Stingless bee propolis, a resinous compound processed by mandibular secretion of stingless bees, is used for maintenance of hygiene and stability of beehives. Research on stingless bee propolis shows therapeutic properties attributed to polyphenols exhibiting antioxidative, antihyperglycemic and antiischemic effect. However, the cardioprotective effect of stingless bee propolis on diabetic cardiomyopathy is unknown. Methods: Adult male Sprague Dawley rats were randomised to five groups: normal group, diabetic group, diabetic given metformin (DM+M), diabetic given propolis (DM+P) and diabetic given combination therapy (DM+M+P) and treated for four weeks. Body weight, fasting blood glucose, food and water intake were taken weekly. At the end of experiment, biomarkers of oxidative damage were measured in serum and heart tissue. Antioxidants in heart tissue were quantified. Part of left ventricle of heart was processed for histological staining including Haematoxylin and Eosin (H&E) stain for myocyte size and Masson's Trichrome (MT) stain for heart fibrosis and perivascular fibrosis. Results: Propolis alleviated features of diabetic cardiomyopathy such as myocyte hypertrophy, heart fibrosis and perivascular fibrosis associated with improvement in antioxidative status. Conclusion: This study reports beneficial effect of propolis and combination with metformin in alleviating histopathological feature of diabetic cardiomyopathy by modulating antioxidants, making propolis an emerging complementary therapy.

Combination of Dendrobium Mixture and Metformin Curbs the Development and Progression of Diabetic Cardiomyopathy by Targeting the lncRNA NEAT1

OBJECTIVES: This study aimed to explore the efficacy of combination treatment with dendrobium mixture and metformin (Met) in diabetic cardiomyopathy (DCM) and its effects on NEAT1 and the Nrf2 signaling pathway. METHODS: H9c2 cells were maintained in medium supplemented with either low (5.5 mmol/L) or high (50 mmol/L) glucose. Male Sprague-Dawley rats were fed a high-glucose diet and administered a single, low dose of streptozotocin (35 mg/kg) via intraperitoneal injection to induce the development of DM. After induction of DM, the rats were treated with dendrobium mixture (10 g/kg) and Met (0.18 g/kg) daily for 4 weeks. Next, quantitative reverse transcription (qRT)-PCR and western blotting were performed to evaluate the expression levels of target genes and proteins. Flow cytometry was performed to assess apoptosis, and hematoxylin and eosin staining was performed to evaluate the morphological changes in rat cardiac tissue. RESULTS: In patients with diabetes mellitus (DM) and myocardial cells and heart tissues from rats with high glucose-induced DM, NEAT1 was downregulated, and the expression levels of Nrf2 were decreased (p<0.01, p<0.001). The combination of dendrobium mixture and Met upregulated the expression of NEAT1 which upregulated Nrf2 by targeting miR-23a-3p, resulting in reduced apoptosis and improved cardiac tissue morphology (p<0.01, p<0.001). CONCLUSION: Dendrobium mixture and Met upregulated the expression of NEAT1 in DCM, thereby inhibiting apoptosis of myocardial cells.

Bibliometric analysis of publications in diabetic cardiomyopathy from 2000 to 2020 based on Web of Science / 中华内分泌代谢杂志

Objective:Based on knowledge visualization analysis to explore the progress of diabetic cardiomyopathy from 2000 to 2020.Methods:Literatures related to diabetic cardiomyopathy indexed in Web of Sciences databases ranging from 2000 to 2020 were collected. Excel, VOSviewer, and CiteSpace 5.0.R1 software were used for visual analysis of countries, research institutions, authors, keywords and related citations.Results:A total of 2 536 articles were collected preliminarily. China has published the most articles in this field through visualization. A total of 909 related articles have been published in the past 20 years, and China has been closely communicated internationally. The United States and Canada ranked the second and the third respectively, totaling 723 and 201. For the distribution of research institutions, the University of Louisville ranked first with 86 articles. A few top high-impact authors, such as Lu Cai and Tan Yi, are from this institution and have published the most articles, indicating that the University of Louisville can be regarded as an international academic center in the field of diabetic cardiomyopathy. Domestic Jilin University and Shandong University followed, ranking the second and the third with 70 and 66 papers respectively. Keyword co-occurrence analysis shows that research hotspots in this field at home and abroad mainly focus on the investigation of the clinical manifestations and pathogenesis of diabetic cardiomyopathy. Finally, through the co-cited literature network, cluster #4 (SGLT-2 inhibitor) is still in evolvement. The development process shows that the treatment is a new trend in the field of diabetic cardiomyopathy research.Conclusions:Knowledge visualization analysis can visually exhibit the intellectual structure, evolution process, hotspots and trending in the field of diabetic cardiomyopathy research. The results showed that the main research power was located in the China, but the cooperation among personnel needs to be strengthened. The future research trend is mainly focused on the treatment of diabetic cardiomyopathy.