Lipoprotein (a)-Related Inflammatory Imbalance: A Novel Horizon for the Development of Atherosclerosis.

PURPOSE OF REVIEW: The primary objective of this review is to explore the pathophysiological roles and clinical implications of lipoprotein(a) [Lp(a)] in the context of atherosclerotic cardiovascular disease (ASCVD). We seek to understand how Lp(a) contributes to inflammation and arteriosclerosis, aiming to provide new insights into the mechanisms of ASCVD progression. RECENT FINDINGS: Recent research highlights Lp(a) as an independent risk factor for ASCVD. Studies show that Lp(a) not only promotes the inflammatory processes but also interacts with various cellular components, leading to endothelial dysfunction and smooth muscle cell proliferation. The dual role of Lp(a) in both instigating and, under certain conditions, mitigating inflammation is particularly noteworthy. This review finds that Lp(a) plays a complex role in the development of ASCVD through its involvement in inflammatory pathways. The interplay between Lp(a) levels and inflammatory responses highlights its potential as a target for therapeutic intervention. These insights could pave the way for novel approaches in managing and preventing ASCVD, urging further investigation into Lp(a) as a therapeutic target.

Application of hyperbaric oxygen therapy in diabetic foot ulcers: A meta-analysis.

Hyperbaric oxygen therapy (HBOT) has been used in patients with diabetic foot ulcers (DFU) for many years, but its clinical efficacy is still controversial. Therefore, this study explored the efficacy of HBOT applied to DFU by means of meta-analysis. PubMed, Cochrane Library, Embase, CNKI and Wanfang databases were searched, from database inception to October 2023, and published randomised controlled trials (RCTs) of HBOT in DFU were collected. Two investigators independently screened the collected literature, extracted relevant data and assessed the quality of the literature. Review Manager 5.4 software was applied for data analysis. Twenty-nine RCTs with 1764 patients were included. According to the combined results, when compared with conventional treatment, HBOT significantly increased the complete healing rate of DFUs (46.76% vs. 24.46%, odds ratio [OR]: 2.83, 95% CI: 2.29-3.51, p < 0.00001) and decreased the amputation rate (26.03% vs. 45.00%, OR: 0.41, 95% CI: 0.18-0.95, p = 0.04), but the incidence of adverse events was significantly higher in patients (17.37% vs. 8.27%, OR: 2.49, 95% CI: 1.35-4.57, p = 0.003), whereas there was no significant difference in the mortality (6.96% vs. 12.71%, OR: 0.52, 95% CI: 0.21-1.28, p = 0.16). Our results suggest that HBOT is effective in increasing the complete healing rate and decreasing the amputation rate in patients with DFUs, but increases the incidence of adverse events, while it has no significant effect on mortality.

[Mouse immune responses elicited by eukaryotic expression plasmid and prokaryotically expressed protein of Brugia malayi myosin 29 epitope].

Objective: To determine the immune responses elicited in BALB/c mice by vaccination with eukaryotic expression plasmid pcDNA3.1(+)-BmM29 containing Brugia malayi myosin 29(BmM29) epitode and prokaryotically expressed recombinant BmM2 protein(rBmM29) respectively. Methods: rBmM29 protein was expressed in E. coli strain BL21, purified as recombinant protein vaccine, and administered via multiple subcutaneous injections. The purified recombinant plasmid pcDNA3.1(+)-BmM29 was used as the nucleic acid vaccine and injected into the tibialis anterior muscle. Sixty BALB/c mice were randomized to receive three immunizations(with intervals of 2 weeks) with PBS (100 µg, group A), pcDNA3.1(+)/CpG (100 µg/30 µg, group B), pcDNA3.1(+)-BmM29/CpG (100 µg/30 µg, group C), rBmM29/CpG(50 µg/30 µg, group D), or pcDNA3.1(+)-BmM29/rBmM29/CpG (two injections of pcDNA3.1(+)-BmM29/CpG 100 µg/30 µg followed by a rBmM29/CpG 50 µg/30 µg). Serum was prepared through ophthalmectomy at week 4, 6, and 8 after primary immunization, and the serum IgG titer was determined by ELISA. The mice were sacrificed at week 8, splenocyte suspension cultured for 48 h, and levels of INF-γ and IL-4 in the supernatant detected by ELISA. Results: ELISA results showed that the A490 values of serum IgG in groups A-E were 0.038 ± 0.050,0.053 ± 0.009,0.360 ± 0.035,0.456 ± 0.025,0.370 ± 0.025 at week 4,0.045 ± 0.003,0.045 ± 0.005,0.510 ± 0.018,0.548 ± 0.010,0.552 ± 0.018 at week 6, and 0.041 ± 0.004,0.044 ± 0.009,0.606 ± 0.047,0.674 ± 0.042,0.770 ± 0.041 at week 8, significantly higher in groups C, D and E than in groups A and B (P < 0.05) at all time points, and significantly higher in group E than in groups C and D(P < 0.05) at week 8. The IFN-γ levels in splenocyte culture supernatant at week 8 after primary immunization were (47.72 ± 8.94),(50.43 ± 2.81),(304.78 ± 8.42),(242.28 ± 5.99), and(426.52 ± 6.76) pg/ml in groups A-E, respectively, significantly higher in groups C-D than in groups A and B(P < 0.05), and in group E than in groups C and D(P < 0.05). The IL-4 levels in splenocyte culture supernatant were(60.00 ± 11.14),(57.71 ± 15.95),(93.17 ± 12.56),(96.67 ± 11.48), and (101.17 ± 5.81) pg/ml, significantly higher in groups C-D than in groups A and B(P < 0.05). Conclusion: Both the recombinant plasmid pcDNA3.19(+)-BmM29 and rBmM29 protein could elicit specific humoral and cellular immune responses in mice. Combined immunization with nucleic acid vaccine and protein vaccine is superior to each of the two alone.

Role of pyroptosis in diabetic cardiomyopathy: an updated review.

Diabetic cardiomyopathy (DCM), one of the common complications of diabetes, presents as a specific cardiomyopathy with anomalies in the structure and function of the heart. With the increasing prevalence of diabetes, DCM has a high morbidity and mortality worldwide. Recent studies have found that pyroptosis, as a programmed cell death accompanied by an inflammatory response, exacerbates the growth and genesis of DCM. These studies provide a theoretical basis for exploring the potential treatment of DCM. Therefore, this review aims to summarise the possible mechanisms by which pyroptosis promotes the development of DCM as well as the relevant studies targeting pyroptosis for the possible treatment of DCM, focusing on the molecular mechanisms of NLRP3 inflammasome-mediated pyroptosis, different cellular pyroptosis pathways associated with DCM, the effects of pyroptosis occurring in different cells on DCM, and the relevant drugs targeting NLRP3 inflammasome/pyroptosis for the treatment of DCM. This review might provide a fresh perspective and foundation for the development of therapeutic agents for DCM.

[Construction of eukaryotic recombinant plasmid of periodic Brugia malayi CPI gene and its immunity].

OBJECTIVE: To observe the immune responses elicited in BALB/c mice by DNA vaccine encoding cysteine protease inhibitor (CPI) of periodic Brugia malayi cloned in vector pcDNA3.1. METHODS: Specific primers were designed on the basis of known sequences of CPI gene from periodic B. malayi. The desired gene fragment was amplified by PCR from cDNA, inserted into cloning vector, pGEM-T, and sub-cloned into pcDNA3.1 to construct pcDNA3.1-BmCPI Forty-eight mice were randomly divided into 4 groups, i.e. normal control group, pcDNA3.1(+) group, pcDNA3.1-BmCPI group, and pcDNA3.1-BmCPI/CpG group injected with PBS 100 microl, pcDNA3.1 100 microg, pcDNA3.1-BmCPI 100 microg and pcDNA3.1-BmCPI 100 microg+CpG 30 microg, respectively on left hind leg of each mouse. All mice received three immunizations with 2-week interval. At the 4th week after the last immunization the muscle around injection spot was collected, in which the level of BmCPI mRNA was detected by RT-PCR. The stimulation index (SI) of spleen lymphocytes was measured by MTI method and the levels o f secreted IL-4 and IFN-gamma in serum were detected by ELISA. RESULTS: The recombinant plasmid pcDNA3.1-BmCPI was constructed and the length of the gene fragment was 621 bp. The results showed that BmCPI gene in the muscle of the immunized mice was detected by PCR. At the 4th and 6th weeks after immunization, the SI of the two immunized groups was significantly higher than normal control group and pcDNA3.1(+) group (53.789 +/- 1.937, 59.735 +/- 4.139, and 61.975 +/- 1.029) (P < 0.05). No significant difference existed between pcDNA3.1BmCPI group and pcDNA3.1-BmCPI/CpG group (P > 0.05). Serum IFN-gamma in pcDNA3.1-BmCPI group and pcDNA3.1-BmCPI/ CpG group increased from the 2nd to the 6th week after the last immunization with the value of 69.544 +/- 3.145 and 106.069 +/- 7.518, 120.019 +/- 5.968 and 136.229 +/- 7.198, 149.109 +/- 2.700 and 178.429 +/- 1.126, respectively. The levels of IFN-gamma in serum from the immunized mice were significantly higher than those of normal control group and pcDNA3.1(+) group (28.264 +/- 1.129, 35.179 +/- 1.029, and 40.110 +/- 1.176, respectively) (P < 0.05). There was a significant difference between the two immunized groups at the 2nd and the 6th weeks after the last immunization (P < 0.05). The level of IL-4 in serum from the immunized mice was significantly higher than those of normal control group and pcDNA3.1(+) group at the 4th and the 6th weeks after the last immunization (P < 0.05). No significant difference was noted in IL-4 level between pcDNA3.1-BmCPI group and pcDNA3.1-BmCPI/CpG group (P > 0.05). CONCLUSION: The recombinant eukaryotic plasmid pcDNA3.1-BmCPI was transcribed in vivo and elicited immune responses in mice.

Effects of Ang â ¡ perfusion on transmural heterogeneous of Cx43 in acute myocardial ischemia reperfusion.

OBJECTIVE: To observe the effects of angiotensin Ⅱ(Ang Ⅱ) perfusion on transmural heterogeneity of Cx43 expression in the rabbit model with acute myocardial ischemia reperfusion (MIR), and investigate the role of rennin-angiotensin system in malignant ventricular arrhythmia induced by MIR. METHODS: Twenty rabbits were randomly divided into MIR group (n = 10) and Ang Ⅱ group (n = 10). MIR model was produced with traditional ligation and opening of the anterior descending coronary artery in all animal. The hearts in vitro in the MIR group and the Ang Ⅱ group were perfused with simply improved Tyrode's solution and containing Ang Ⅱ Tyrode's solution respectively. 90% monophasic action potential repolarization duration, transmural dispersion of repolarization, Cx43 protein (Cx43-pro) and mRNA (Cx43-Cq) expression in subepicardial, midmyocardial and subendocardial myocardium were measured in both groups. The greatest differences of Cx43-pro and Cx43-Cq among three myocardial layers were calculated and shown with ΔCx43-pro and ΔCx43-Cq respectively. RESULTS: After Ang Ⅱ perfusion, 90% monophasic action potential repolarization duration among three myocardial layer were significantly prolonged (P < 0.05 and P < 0.01), and transmural dispersion of repolarization also significantly increased compared with the MIR group (P < 0.05). Compare with the MIR group, three myocardial Cx43-pro and Cx43-Cq expression in the Ang Ⅱ group were significantly decreased (P < 0.05 and P < 0.01), but ΔCx43-pro and ΔCx43-Cq were significant increased. CONCLUSIONS: Renin-angiotensin system increases transmural heterogeneity of Cx43 expression in the rabbit model with MIR by Ang Ⅱ, and enlarge transmural dispersion of repolarization among three myocardial layers of left ventricular which induces malignant ventricular arrhythmia.

A randomized, double blind, placebo-controlled, multicenter phase II trial of Allisartan Isoproxil in essential hypertensive population at low-medium risk.

BACKGROUND: Angiotensin II receptor blockers (ARBs) is a well-tolerated class of antihypertensive agents, exhibiting effective antihypertensive and cardiovascular protective function. The objective of the study was to examine the efficacy and safety of Allisartan Isoproxil, a newly developed, selective, nonpeptide blocker of the angiotensin II type 1 receptor (AT1R), in essential hypertensive patients at low-medium risk. METHODS AND FINDINGS: A Phase II prospective, randomized, double-blind, placebo-controlled, multicenter trial comparing Allisartan Isoproxil 240mg versus placebo was conducted in essential hypertensive patients at low-medium risk at 8 sites in China. After a 2-week placebo baseline period, 275 patients received once-daily treatment with Allisartan Isoproxil 240mg or placebo randomly for 8 weeks. Systolic/diastolic blood pressure (SBP/DBP) was measured at week 2, 4 and 8. By the end of treatment, mean reductions from baseline of SBP and DBP in Allisartan Isoproxil and placebo groups were 14.5/10.4 and 8.3/7.7 mmHg, respectively (P<0.01). The rate of effective blood pressure control in Allisartan Isoproxil group was significantly higher than in placebo group at week 4 (61.3% vs 50.0%, P<0.05) and week 8 (67.2% vs 48.6%, P<0.01). In terms of safety and tolerability, there were no report of death and serious adverse event (SAE) in all subjects. There was no difference of frequency between two groups in adverse event (AE) and adverse drug reaction (ADR) (P>0.05). No one withdraw because of an ADR in two groups. 124 patients received additional 56 weeks treatment with Allisartan Isoproxil and 84 of them completed the study. The rate of effective BP control kept up to 80% since week 24. No significant clinical change was observed and ADRs were generally mild or moderate during the long-term study. CONCLUSIONS/SIGNIFICANCE: Allisartan Isoproxil 240mg was effective and safe for essential hypertension patients at low-medium risk. TRIAL REGISTRATION: http://www.chictr.org/cn/ ChiCTR-TRC-10000886.

Comparative analysis of different cyclosporine A doses on protection after myocardial ischemia/reperfusion injury in rat.

OBJECTIVE: To investigate the protective effect of different cyclosporin A (CsA) doses on myocardial ischemia/reperfusion injury in rat models. METHODS: A rat model of myocardial ischemia/reperfusion injury was established in vivo and the rats were randomly divided into four groups: placebo (PBS; T1), low-dose (CsA dose: 1.0 mg/kg; T2), medium-dose (CsA dose: 2.5 mg/kg; T3), and high-dose (CsA dose: 5.0 mg/kg; T4) groups. Heart function indexes were monitored at different time points, the extent of myocardial infarction was assessed by Evans Blue-TTC staining, and creatine kinase MB mass and cardiac troponin I values were measured by biochemical assays. RESULTS: Compared with the T1 and T2 groups, both the creatine kinase MB mass and cardiac troponin I were significantly lower in the T3 and T4 groups (P<0.05). The mean arterial pressure (MAP) and left ventricular systolic pressure (LVSP) decreased sequentially in each group, with the extending reperfusion time. Significant decreases in LVSP and MAP were observed in the T3 and T4 groups as compared to the T1 and T2 group (P<0.05), and the T2 group showed a significantly lower LVSP and MAP decline than the T1 group (P<0.05). Compared with the T1 group, the rats from the T2, T3, and T4 groups suffered from a significantly lower extent of myocardial infarction (P<0.05). Also, the animals in the T3 and T4 groups had a significantly smaller extent of myocardial infarction than those in the T2 group (P<0.05). CONCLUSIONS: Various CsA doses exert different degrees of protection against ischemia/reperfusion injury, and this protective effect peaks at approximately 2.5 mg/kg in rat models.

Effects of hypokalemia on transmural dispersion of ventricular repolarization in left ventricular myocardium.

OBJECTIVE: To observe effects of hypokalemia on transmural heterogeneity of ventricular repolarization in left ventricular myocardium of rabbit, and explore the role of hypokalemia in malignant ventricular arrhythmia (MVA). METHODS: A total of 20 rabbits were randomly divided into control group and hypokalemic group. Isolated hearts in the control group were simply perfused with modified Tyrode's solution, and were perfused with hypokalemic Tyrode's solution in hypokalemic group. Ventricular fibrillation threshold (VFT), 90% monophasic action potential repolarization duration (APD90) of subepicardial, midmyocardial and subendocardial myocardium, transmural dispersion of repolarization (TDR) and C×43 protein expression in three layers of myocardium were measured in both groups. RESULTS: VFT in the control group and the hypokalemic group were (13.40 ± 2.95) V, and (7.00 ± 1.49) V, respectively. There was a significant difference between two groups (P<0.01). APD90 of three myocardial layers in the hypokalemic group were significantly prolonged than those in the control group (P<0.01). ΔAPD90 in the hypokalemic group and the control group were (38.10 ± 10.29) ms and (23.70 ± 5.68) ms, and TDR were (52.90 ± 14.55) ms and (36.10 ± 12.44) ms, respectively. ΔAPD90 and TDR in the hypokalemic group were significantly higher than those in the control group (P<0.05), and the increase in APD90 of midmyocardium was more significant in the hypokalemic group. Cx43 protein expression of all three myocardial layers were decreased significantly in the hypokalemic group (P<0.01), and ΔCx43 was significantly increased (P<0.05). Reduction of Cx43 protein expression was more significant in the midmyocardium. CONCLUSIONS: Hypokalemic can increase transmural heterogeneity of C×43 expression and repolarization in left ventricular myocardium of rabbit, and decrease VFT and can induce MVA more easily.