Polygonatum sibiricum (Huang Jing) polysaccharide reduces diabetic cardiomyopathy through increasing cyclic guanosine monophosphate-protein kinase G signaling in diabetic mice.

AIMS/INTRODUCTION: Diabetic cardiomyopathy (DCM) is a prevalent condition among individuals with diabetes, and is associated with a high mortality rate. The anti-oxidant properties of Jing Huang or Polygonatum sibiricum polysaccharide (PSP) have been extensively used to treat diabetes-related disorders; however, its potential effectiveness against DCM remains unknown. This study aimed to investigate PSP's therapeutic effects on DCM in an experimental diabetic mouse model. MATERIALS AND METHODS: To induce insulin resistance, mice were fed a high-fat diet for 3 months, followed by intraperitoneal streptozotocin injection to induce slight hyperglycemia and develop DCM. Both DCM and control mice were given PSP orally for 3 weeks. Western blotting was used to detect the protein expressions of protein kinase G, C/EBP homologous protein, glucose-regulated protein 78, phosphodiesterase type 5, protein kinase R-like endoplasmic reticulum (ER) kinase, and phospho-protein kinase R-like endoplasmic reticulum kinase in heart tissue. RESULTS: The results showed a reduction in bodyweight and blood glucose levels in the PSP therapy group compared with DCM group. PSP also improved cardiac function and had a negligible effect on malondialdehyde activity. Furthermore, the findings showed that PSP alleviated ER and oxidative stress observed in DCM mice hearts, leading to the inhibition of cyclic guanosine monophosphate-specific phosphodiesterase type 5 and cardiac cyclic guanosine monophosphate reactivation. Phosphodiesterase type 5 inhibition reduced high-fat diet-induced cardiac dysfunction and decreased ER stress. CONCLUSIONS: PSP could effectively protect diabetic myocardium by inhibiting endoplasmic reticulum stress. These findings provide crucial insights into the potential of PSP to ameliorate DCM conditions in diabetic mice by decreasing ER and oxidative stress, and enhancing cyclic guanosine monophosphate protein kinase G signaling.

Obese mice induced by high-fat diet have differential expression of circular RNAs involved in endoplasmic reticulum stress and neuronal synaptic plasticity of hippocampus leading to obesity-associated cognitive impairment.

Obesity induced by a high-fat diet (HFD) is an important cause of impaired memory and cognitive function, but the underlying mechanisms are not clear. In the present study, we analyzed the levels of circRNAs in the hippocampus of C57BL/6J mice and evaluated the memory and cognition ability of C57BL/6J mice with HFD using Morris water maze and Y-maze approaches to explore the potential mechanisms linking circRNAs in obesity-associated cognitive impairment. Learning performance showed that HFD-induced obesity mice have impaired memory and cognition. The Arraystar analysis of the hippocampus displayed that HFD-induced obesity leads to the differential expression of circRNAs (DE-circRNAs) in mice. In total, 46 circular RNAs with elevated expression and 10 with decreased expression were identified. Among them, mmu_circRNA_004797 was identified to be significantly downregulated and the expression of mmu_circRNA_21040 was significantly upregulated in the HFD-fed mice, compared with control mice by PCR test. Bioinformatics analysis also showed that the upregulated circRNAs were related to the neuronal function and behavior, and material transport process, while downregulated circRNAs participated in the process of cell response to external stimuli, such as cellular response to nutrient levels. Furthermore, the KEGG pathway analysis showed that the upregulated circRNAs are mainly involved in Axon guidance, calcium signaling pathway, and ErbB signaling pathway. Only a single significant pathway, that is, "protein processing in endoplasmic reticulum", was observed in the downregulated circRNAs. Finally, we examined the deficits of hippocampal synaptic plasticity and detected the expression of ER stress-related protein. The results showed that ER stress was activated in the hippocampus, and hippocampal synaptic plasticity deficits were displayed. Our results demonstrated that circRNAs were most likely implicated in the predisposition to obesity-associated cognitive impairment.

Cardioprotective effects of corilagin on doxorubicin induced cardiotoxicity via P13K/Akt and NF-κB signaling pathways in a rat model.

Even though doxorubicin (DOX) is a potential chemotherapeutic drug, its usage is restricted due to its ability to induce cardiac damage. In order to prevent this damage, a potent cardioprotective agent should be associated with DOX treatment. Corilagin is a natural polyphenol tannic acid which unveils enormous pharmacological activities predominantly as an antitumor agent. Hence, the current work is designed to study the precise mechanisms of corilagin upon administration in doxorubicin induced cardiotoxicity in experimental rats. DOX treated rats showed diminished level of blood pressures and heart rate, whereas corilagin along with DOX treatment improved the status. Cardiotoxicity enzymes and biomarkers were found to be increased in the serum of DOX induced rats. Upon treatment, corilagin could reduce the cardiotoxicity enzymes and biomarkers in serum. Histopathological examination of cardiac tissue also revealed the anti-toxic effects of corilagin in contrast to DOX. Injection of DOX in rats showed inflammatory cells infiltration, necrosis and fragmented myofibrils. Corilagin treatment reverted the cardiac histology to near normal. Inflammatory mediators and P13K, Akt, and NF-κB were upregulated in DOX administered rats. Corilagin repressed the levels of P13K, Akt, and NF-κB in DOX induced rats. In the present investigations, corilagin improved cardiac function via reducing injury, inflammation and promoting apoptosis thereby suggesting that corilagin would be recommended for DOX-induced cardiotoxicity.

Metabonomics Analysis of Myocardial Metabolic Dysfunction in Patients with Cardiac Natriuretic Peptide Resistance.

Brain natriuretic peptide (BNP) is an important biological marker and regulator of cardiac function. BNP resistance is characterized by high concentrations of less functionally effective BNP and common in heart failure (HF) patients. However, the roles and consequences of BNP resistance remain poorly understood. Investigate the effects of cardiac BNP resistance and identify potential metabolic biomarkers for screening and diagnosis. Thirty patients and thirty healthy subjects were enrolled in this study. Cardiac functions were evaluated by echocardiography. The plasma levels of cyclic guanosine monophosphate (cGMP) and BNP were measured by enzyme-linked immunosorbent assay (ELISA) and the cGMP/BNP ratio is calculated to determine cardiac natriuretic peptide resistance. Liquid chromatograph tandem mass spectrometry (LC-MS) based untargeted metabolomics analysis was applied to screen metabolic changes. The cGMP/BNP ratio was markedly lower in HF patients than controls. The cGMP/BNP ratio and ejection fraction (EF) were strongly correlated (R 2 = 0.676, P < 0.05). Importantly, metabolic profiles were substantially different between HF patients and healthy controls. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated that the differentially expressed metabolites are involved in signaling pathways that regulate cardiac functions. In HF patients, BNP resistance develops in association with a reduction in heart function and metabolic remodeling. It suggests possible functional roles of BNP resistance in the regulation of cardiac metabolism.

[Total flavonoids in Scutellaria barbata prevents NLRP3 inflammasome expression in tumor cells by affecting autologous pathway].

This paper was aimed to investigate the relationship between autophagy and NLRP3 inflammasome activation by studying the effect oftotal flavonoids in Scutellaria barbata (TF-SB) on autophagy in tumor cells and NLRP3 inflammasome, and to provide experimental evidence for further study of the anti-tumor mechanism of TF-SB. Mielanoma models were established by inoculating B16-F1 cell line to mice, and then were randomly divided into 5 groups (n=10 in each group): model control, positive control control(Rap, 1.5 mg•kg⁻¹), and TF-SB low, middle and high groups (50, 100 and 200 mg•kg⁻¹). Meanwhile, healthy C57BL/6J mice were used as normal control group (n=10). The drugs were given once daily for 2 weeks consecutively. Thirty minutes after last treatment, the determinations at endpoint were performed; pathological changes of tumor tissue were evaluated by using HE staining; protein expressions of LC3-II/LC3-I or NLRP3inflammasome/caspase-1/IL-1ß and IL-18 in tumor tissues were detected by using Western-blot; and serum levels of IL-1ß and IL-18 were detected by using Elisa kit. The results showed that the tumor cells in model group showed obvious atypia and malignant proliferation; the invasion of tumor tissue was significantly reduced, the tumor necrosis area was significantly increased, and the inflammatory reaction was significantly alleviated in positive control group and various TF-SB groups. As compared with model control group, LC3-II/LC3-I was significantly increased, while NLRP3/caspase-1/IL-1ßand IL-18 protein expressions were significantly decreased in positive control group and TF-SB groups. Serum IL-1ß and IL-18 levels in model control group were found higher than those in control group (P<0.001), but they were significantly lowered in positive control group and TF-SB groups (P<0.05, P<0.01 or P<0.001). Taken together, total flavonoids in S. barbata could effectively alter the tumor growth micro-environment by inhibiting the expression of NLRP3 inflammasome, and its anti-tumor effect may be associated with the induction of tumor cell autophagy.