# Old and Novel Predictors for Cardiovascular Risk in Diabetic Foot Syndrome--A Narrative Review
## 6 Future Directions
### Novel Therapeutic Targets  
Advances in technology have enabled advanced clinical research, and various signaling pathways are currently being investigated for future use in the development of targeted therapeutic molecules [180]. P38 kinases are considered valuable and promising therapeutic targets in preventing the onset or progression of diabetic cardiomyopathy based on p38-MAPK-generated inhibition that resulted in improved inflammatory status and systolic function in previous animal studies of diabetic mice [242]. The use of phosphodiesterase type 5 inhibitors may prevent hyperglycemia-induced changes in cardiomyocyte gene expression, thereby counteracting the increased cyclic adenosine 5-monophosphate-responsive element modulator [243].  
Modulation of nuclear factor erythroid 2-related factor 2 activity is associated with decreased inflammation and lipid accumulation or prevention of the development of fibrosis secondary to DM, thus representing a potential therapeutic target in patients with diabetic cardiomyopathy [244]. The use of exosomes developed from heat shock protein 20 has been shown in animal studies to modulate the secretory activity of cardiomyocytes [245]. microRNAs and the correction of intestinal dysbiosis interfere with the pathophysiological processes of diabetic cardiomyopathy [246]. In a previous clinical study, [PERSON] et al. [247] demonstrated that anti-miR1 induces survival signals in cardiac progenitor cells or cardiomyocytes subjected to permanent hyperglyic status.  
Gene therapy is a very promising future research direction in relation to DM and DFS. To date, pre-clinical research with murine leukemia virus-1 (PIM-1) via cardiotropicserotype-9 adeno-associated virus (AAV) which increased PIM-1 expression and cardiac phosphoinositide 3-kinase using AAV6 has demonstrated in vitro prevention of cardiac apoptosis, fibrosis or development of heart failure and increased LV systolic function in diabetic mice [176; 178; 247].  
The Charcot DF is frequently encountered in patients with DM, being one of the most disabling and severe complications [248]. The pathophysiology is complex and multifactorial, involving numerous signaling pathways and molecules that mediate diverse, interconnected processes that over time result in osteolysis and ultimately bone destruction [249; 250]. One such example is the receptor activator of the NF-kB ligand receptor activator of NF-kB osteoproteger (RANKL-RANK-OPG) pathway which modulates inflammatory processes, its overexpression and activation being accompanied by increased osteoclast activity and osteolysis [251]. Taking into account the role of this signaling pathway in bone remodeling in patients with DFS, several therapeutic agents have been developed to act at different levels of the signaling pathway with the aim of halting the disabling progression of Charcot DF [251]. One such example is the administration of anti-RANKL monoclonal antibodies such as Denosumab, which--although it has, so far, been studied in small groups of patients--has encouraging results that justify further research in larger groups of patients [252; 253; 254; 255].  
In terms of wound healing, previous clinical and animal studies have demonstrated that ulcer-associated pro-inflammatory status, lack of ischemia correction and lesion maturation are therapeutic targets associated with improved wound healing in patients with DFS [255]. The neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio are two easily measurable, reproducible inflammatory biomarkers with prognostic value in both the onset and progression of DFS. Among patients with DF-associated infections, elevated values of these biomarkers correlate with the occurrence of osteomyelitisitis, the need for amputation or septic complications [256; 257].