Dipeptidyl peptidase 4 (DPP-4) inhibitors (commonly referred to as gliptins) are a novel class of oral antihyperglycaemic agents with demonstrated efficacy in the treatment of type 2 diabetes mellitus (T2DM). Preclinical data and mechanistic studies have indicated a possible beneficial action on blood vessels and the heart, via both glucagon-like peptide 1 (GLP-1)-dependent and GLP-1-independent effects. DPP-4 inhibition increases the concentration of many peptides with potential vasoactive and cardioprotective effects. Clinically, DPP-4 inhibitors improve several risk factors in patients with T2DM. They improve blood glucose control (mainly by reducing postprandial glycaemia), are weight neutral (or even induce modest weight loss), lower blood pressure, improve postprandial lipaemia, reduce inflammatory markers, diminish oxidative stress, and improve endothelial function. Some positive effects on the heart have also been described in patients with ischaemic heart disease or congestive heart failure, although their clinical relevance requires further investigation. Post-hoc analyses of phase II-III, controlled trials suggest a possible cardioprotective effect with a trend for a lower incidence of major cardiovascular events with gliptins than with placebo or active agents. However, the actual relationship between DPP-4 inhibition and cardiovascular outcomes remains to be proven. Major prospective clinical trials with predefined cardiovascular outcomes and involving various DPP-4 inhibitors are now underway in patients with T2DM and a high-risk cardiovascular profile.

Cardiovascular effects of gliptins

The incretin hormone, glucagon-like peptide-1 (GLP-1), stimulates insulin secretion and forms the basis of a new drug class for diabetes treatment. GLP-1 has several extra-pancreatic properties which include effects on kidney function. Although renal GLP-1 receptors have been identified, their exact localization and physiological role are incompletely understood. GLP-1 increases natriuresis through inhibition of the sodium-hydrogen ion exchanger isoform 3 in the proximal tubule. This may in part explain why GLP-1 receptor agonists have antihypertensive effects. Glomerular filtration rate is regulated by GLP-1, but the mechanisms are complex and may depend on e.g. glycaemic conditions. Atrial natriuretic peptide or the renin-angiotensin system may be involved in the signalling of GLP-1-mediated renal actions. Several studies in rodents have shown that GLP-1 therapy is renoprotective beyond metabolic improvements in models of diabetic nephropathy and acute kidney injury. Inhibition of renal inflammation and oxidative stress probably mediate this protection. Clinical studies supporting GLP-1-mediated renal protection exist, but they are few and with limitations. However, acute and chronic kidney diseases are major global health concerns and measures improving renal outcome are highly needed. Therefore, the renoprotective potential of GLP-1 therapy need to be thoroughly investigated in humans.

Effects of GLP-1 in the kidney.

Recent advances have greatly improved our understanding of the molecular mechanisms behind atherosclerosis pathogenesis. However, there is still a need to systematize this data from a general pathology perspective, particularly with regard to atherogenesis patterns in the context of both canonical and non-classical inflammation types. In this review, we analyze various typical phenomena and outcomes of cellular pro-inflammatory stress in atherosclerosis, as well as the role of endothelial dysfunction in local and systemic manifestations of low-grade inflammation. We also present the features of immune mechanisms in the development of productive inflammation in stable and unstable plaques, along with their similarities and differences compared to canonical inflammation. There are numerous factors that act as inducers of the inflammatory process in atherosclerosis, including vascular endothelium aging, metabolic dysfunctions, autoimmune, and in some cases, infectious damage factors. Life-critical complications of atherosclerosis, such as cardiogenic shock and severe strokes, are associated with the development of acute systemic hyperinflammation. Additionally, critical atherosclerotic ischemia of the lower extremities induces paracoagulation and the development of chronic systemic inflammation. Conversely, sepsis, other critical conditions, and severe systemic chronic diseases contribute to atherogenesis. In summary, atherosclerosis can be characterized as an independent form of inflammation, sharing similarities but also having fundamental differences from low-grade inflammation and various variants of canonical inflammation (classic vasculitis).

/pdf/atherosclerosis-and-inflammation-insights-from-the-theory-of-tglhs1ks.pdf

Atherosclerosis and Inflammation: Insights from the Theory of General Pathological Processes

Targeting endothelial dysfunction and inflammation.

Abstract Cardiovascular diseases (CVDs) continue to exert a significant impact on global mortality rates, encompassing conditions like pulmonary arterial hypertension (PAH), atherosclerosis (AS), and myocardial infarction (MI). Oxidative stress (OS) plays a crucial role in the pathogenesis and advancement of CVDs, highlighting its significance as a contributing factor. Maintaining an equilibrium between reactive oxygen species (ROS) and antioxidant systems not only aids in mitigating oxidative stress but also confers protective benefits on cardiac health. Herbal monomers can inhibit OS in CVDs by activating multiple signaling pathways, such as increasing the activity of endogenous antioxidant systems and decreasing the level of ROS expression. Given the actions of herbal monomers to significantly protect the normal function of the heart and reduce the damage caused by OS to the organism. Hence, it is imperative to recognize the significance of herbal monomers as prospective therapeutic interventions for mitigating oxidative damage in CVDs. This paper aims to comprehensively review the origins and mechanisms underlying OS, elucidate the intricate association between CVDs and OS, and explore the therapeutic potential of antioxidant treatment utilizing herbal monomers. Furthermore, particular emphasis will be placed on examining the cardioprotective effects of herbal monomers by evaluating their impact on cardiac signaling pathways subsequent to treatment. Graphical Abstract 

Targeting oxidative stress as a preventive and therapeutic approach for cardiovascular disease

https://doi.org/10.1016/j.jare.2022.02.017

SOX4 is a novel phenotypic regulator of endothelial cells in atherosclerosis revealed by single-cell analysis

The prevalence of cardiovascular disease (CVD) has been rising due to sedentary lifestyles and unhealthy dietary patterns. Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor regulating multiple biological processes, such as lipid metabolism and inflammatory response critical to cardiovascular homeostasis. Healthy endothelial cells (ECs) lining the lumen of blood vessels maintains vascular homeostasis, where endothelial dysfunction associated with increased oxidative stress and inflammation triggers the pathogenesis of CVD. PPARα activation decreases endothelial inflammation and senescence, contributing to improved vascular function and reduced risk of atherosclerosis. Phenotypic switch and inflammation of vascular smooth muscle cells (VSMCs) exacerbate vascular dysfunction and atherogenesis, in which PPARα activation improves VSMC homeostasis. Different immune cells participate in the progression of vascular inflammation and atherosclerosis. PPARα in immune cells plays a critical role in immunological events, such as monocyte/macrophage adhesion and infiltration, macrophage polarization, dendritic cell (DC) embedment, T cell activation, and B cell differentiation. Cardiomyocyte dysfunction, a major risk factor for heart failure, can also be alleviated by PPARα activation through maintaining cardiac mitochondrial stability and inhibiting cardiac lipid accumulation, oxidative stress, inflammation, and fibrosis. This review discusses the current understanding and future perspectives on the role of PPARα in the regulation of the cardiovascular system as well as the clinical application of PPARα ligands.

Molecular mechanisms and therapeutic perspectives of peroxisome proliferator-activated receptor α agonists in cardiovascular health and disease.

Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Protects Endothelial Function in Hypertension through GLP-1 Dependent Mechanism

Diabetic kidney disease (DKD), a severe diabetic complication affecting approximately one-third of diabetic patients, is the leading cause of end-stage chronic kidney disease. The benefits of regular exercise for patients with DKD have been well documented, particularly in overweight patients with DKD. However, the underlying mechanisms are incompletely understood. The present study demonstrates that exercise improves kidney function in diabetic db/db mice through activating PPAR��-mediated fatty acid ��-oxidation (FAO). Twelve-week treadmill running exercise improved kidney function in db/db mice. Metabolomics and transcriptomics profiling analysis collectively revealed that dysregulation of FAO in db/db mice was largely corrected by running exercise. KEGG pathway enrichment revealed that PPAR pathway, a critical signalling cascade in FAO and exercise, is involved in DKD, suggesting PPAR�� activation protects renal function through promoting FAO. Which was confirmed by improved renal function and enhanced FAO in db/db mice treated with PPAR�� agonist GW501516. Oppositely, PPAR��-specific inhibitor GSK0660 abolished exercise-mediated improvement in renal function and FAO. In combining with gene expression profiling data we identified CPT1��, the rate-limiting enzyme in fatty acid oxidation, was suppressed in the kidney of diabetic mice and reversed by exercise and the PPAR�� agonist GW501516. The findings hint at a potential role for the PPAR��-CPT1�� pathway in exercise-induced improvements in diabetic renal function and may warrant further exploration of the PPAR��-CPT1�� pathway as a therapeutic target in DKD.


Exercise alleviates diabetic kidney disease through PPAR��-CPT1�� pathway-dependent fatty acid ��-oxidation

Review
The Therapeutic Effects of Ligustrazine in Combination with Other Drugs in Cardiovascular Diseases

Peihua Dong , Yu Huang , and Yujie Pu ,*


Department of Biomedical Sciences, City University of Hong Kong, Hong Kong 518057 , China
* Correspondence: yujiepu@cityu.edu.hk
 
 
Received: 29 December 2022
Accepted: 18 January 2023
Published: 10 February 2023
 

Abstract: Chuanxiong, one of the traditional Chinese medicines (TCM), was first documented in the Tang dynasty to promote blood circulation and remove blood stasis. Ligusticum chuanxiong Hort was shown as the most effective portion of chuanxiong. Later chemical analysis revealed that the main chemical component of ligusticum chuanxiong Hort is tetramethylpyrazine. Since then, numerous explorations have been made to examine the efficiency of tetramethylpyrazine in treating different diseases and understand the underlying mechanisms of its action. Like Chuanxiong, ligustrazine (Chuan Xiong Qin) improved the functions of the circulatory and nervous systems. Ligustrazine (Chuan Xiong Qin) was also used in combination with other medicines to achieve better effects on improving cardiovascular health or alleviating the adverse effects of chemotherapies in both basic and clinical studies. The present review briefly summarizes the existing studies of the combination of ligustrazine (Chuan Xiong Qin) with other medicines in the treatment of cardiovascular diseases (CVDs) and provides valuable insights into the future research direction and better utilization of this drug.

/pdf/the-therapeutic-effects-of-ligustrazine-in-combination-with-13e7iskb.pdf

The Therapeutic Effects of Ligustrazine in Combination with Other Drugs in Cardiovascular Diseases

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