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Effects of gemigliptin on adriamycin-induced podocyte loss (a); immunofluorescence stain for WT-1 (red) and DAPI (blue) and double-positive cells (pink) (b); mean podocyte number per glomerulus in each group is presented and shown for DAPI-positive and WT-1 positive cells; the asterisk indicates that the difference in mean podocyte number per glomerulus between groups is significant. p values are obtained using the one-way analysis of variance test followed by Tukey’s post hoc test. ∗p<0.05 compared with (A), †p<0.05 compared with (B), and #p<0.05 compared with (C). GM, gemigliptin; ADR, adriamycin; WT-1, Wilms tumor-1; DAPI, 4′,6-diamidino-2-phenylindole.
Source publication
Background . Previous studies have shown the antiapoptotic and anti-inflammatory potential of DPP-IV inhibitor in experimental models of renal injury. We tested whether DPP-IV inhibitor (gemigliptin) ameliorates renal injury by suppressing apoptosis, inflammation, and oxidative stress in mice with adriamycin nephropathy. Methods . Mice were treated...
Citations
... The rat model of ADR-induced chronic toxicity is characterized by focal glomerulosclerosis (decrease in glomeruli numbers and tuft collapse), severe tubulointerstitial fibrosis, and inflammation [9,10]. The mechanisms involved in ADR-induced nephropathy include the overproduction of free oxygen radicals, suppression of antioxidant gene, nuclear factor erythroid 2-related factor 2 (Nrf2), the activation of inflammatory cytokines, e.g., nuclear factor-kappa beta (NF-B), transforming growth factor (TGF)-beta and interleukin (IL)-6 release and apoptotic pathways are the most likely mechanisms [11][12][13][14][15][16][17][18]. Various antioxidants, anti-inflammatory, or antiapoptotic medicines have been suggested to counteract ADR-induced damages based on these observations. ...
The current study assessed the impact of cerium oxide nanoparticles (nanocerium, NC) on adriamycin (ADR)-induced nephropathy in addition to the physiological role of oxidative stress, Nrf2/HO-1 pathway, apoptosis, TGF-β, and Sirt-1 in its action. Forty adult male Sprague–Dawley rats were divided into four groups as follows: control, NC, ADR, and ADR + NC groups. At the end of the experiment, urine, blood samples, and kidney were taken for assessment of serum creatinine (Cr), blood urea nitrogen (BUN), and urinary protein. Also, malondialdehyde (MDA), reduced glutathione (GSH) and catalase (CAT) levels, histopathological examinations, immunohistochemical examinations for caspase-3, TGF-β, Sirt-1, and real-time PCR for the expression of Nrf2 and HO-1 antioxidant genes in kidney tissues were done. NC significantly improved the raised serum creatinine, BUN, and urinary proteins. Also, NC improved the expression of caspase-3 and markers of oxidative stress in kidney tissues, and it also reduced morphological renal damage. Moreover, NC caused a significant increase in the expression of SIRT1 and Nrf2/HO-1 in kidney tissues. Also, markedly decreased renal fibrosis. Nanocerium alleviates ADR nephropathy, which may be related to the antioxidant and anti-fibrotic action of NC. Also, upregulating and activating SIRT1, Nrf2/HO-1 signaling and reduction of apoptosis.
Graphical Abstract
... Finally, the serum albumin, superoxide dismutase, and glutathione were reduced compared to the control group (15). Some investigators found increased apoptotic and inflammatory agents, alteration of the Bax/Bcl-2 ratio, and high expression of the NF-κB p65 genes in the kidneys of babl/c mice due to DOX toxicity (16)(17)(18). The ischemic injury could be reduced by melatonin administration. ...
Background: Doxorubicin is preferred to cure many malignancies. Its nephrotoxicity is a dangerous nature that is to operate with a warning. Antioxidants accompanied by anticancer could moderate the various side effects. Objectives: Cichorium intybus (C. intybus) has nephron-protective effects. Melatonin stands as an antioxidant equivalent to others. The repairing effects of C. intybus-melatonin against the toxicity effects of doxorubicin on the kidneys were studied. Methods: Thirty 20 g to 25 g, balb/c mice were divided into 5 identical groups (n: 6). The research was grouped as control saline; DOX with the injection of doxorubicin; Chicory with the administration of the C. intybus complete extract following DOX; melatonin with the administration of the melatonin following DOX; both: with the administration of the chicory and melatonin following DOX. The histopathological study was set to determine degeneration, inflammation, and necrosis. Results: The mean of each histological phenomenon in the control group was significantly lower than in the DOX group. In the histopathology, we saw that all the treating groups, including C. intybus extract-received, melatonin-received, both of them received improved better than the doxorubicin-received group. The best improving mean was seen in the latter group. The DOX-induced nephrotoxicity could be improved by using the C. intybus extract and melatonin synchronously as therapeutic care. Conclusions: Synchronous administration of the chicory and melatonin has a healing potency against doxorubicin-induced nephrotoxicity.
... The exact mechanisms underlying the effect of ADR on inflammation are unclear. Studies have shown that there may be an interaction between inflammation and nuclear factor kappa B (NF-KB)(27). It has been proven that NF-κB, an important transcriptional activator, regulates the expression of inflammatory factors(28). ...
Although Adriamycin (ADR) is an important anticancer drug used in chemotherapy, it causes
nephrotoxicity. The inflammation pathway has an important role in ADR-induced
nephrotoxicity. Chloroquine (CLQ), which is used as an antimalarial drug, is used in many
diseases. Also, CLQ is known as an anti-inflammatory. In this study, we aimed to investigate
the effect of CLQ against nephrotoxicity caused by ADR through the inflammatory pathway.
Groups were formed as follows; Control (n = 8), CLQ (n = 8) 50 mg / kg intraperitoneally (i.p.)
per day, ADR (n = 8) 2 mg / kg i.p. every 3 days, ADR + CLQ (n = 8) 2mg / kg / i.p. ADR + 50
mg / kg / i.p. CLQ. The experiment took a total of 30 days. At the end of the experiment, kidney
tissues were taken from the rats under anesthesia. After fixation in the removed kidney tissues,
the tissues were embedded in paraffin by histological methods. Sections were taken from kidney
tissues. Renal tissue histopathology and Tumor necrosis factor-alpha (TNF-α) and Nuclear
factor-κB p65 (NF-κB p65) immunoreactivities were evaluated. When the kidney tissue was
examined, it was seen that damage was caused by ADR. In addition, it was observed that TNFα and NF-κB p65 immunoreactivities in the kidney significantly increased in the ADR group (p
<0.05). Damage and inflammatory markers were found to be decreased in the ADR + CLQ
group (p <0.05). Chemotherapeutically administered ADR appears to cause nephrotoxicity.
CLQ administered was found to reduce this toxicity. As a result, we showed that the damage
caused by ADR-induced nephrotoxicity decreased with the application of CLQ through the
TNF-α and NF-κB p65 inflammation pathway.
Keywords: Adriamycin, Chloroquine, Inflammation, K
... In addition to the glucose-lowering effects of DPP-4 inhibitors, tissue-protective effects of DPP-4 inhibition have been demonstrated in ischemia-reperfusion injury, DKD, and CKD. Kim et al. [18] reported that gemigliptin treatment led to reduced apoptosis, inflammation, and oxidative stress in a murine model of adriamycin-induced nephropathy. Choi et al. [19] showed that gemigliptin attenuated cisplatin-induced renal dysfunction in mice. ...
Introduction. Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control and have pleiotropic effects on kidney injury, albuminuria, and vascular inflammation, especially in animal models. We evaluated the effects of a potent DPP4 inhibitor (gemigliptin) on these processes among patients with diabetic kidney disease (DKD). Methods. This study employed a multicenter, prospective, randomized, placebo-controlled design. A total of 201 participants were enrolled and randomly assigned to one of two groups, one received treatment with 50 mg gemigliptin daily along with standard care for diabetes mellitus for 6 months. The changes in the coronary calcium score (CAC score), cardio-ankle vascular index (CAVI), estimated glomerular filtration rate (eGFR), vascular calcification level, and tubular renal injury marker expression were evaluated at baseline and 6 months. Results. In total, 182 patients completed the study. Significant reductions in hemoglobin A1C levels were observed in both groups. The changes in the CAC score, CAVI, eGFR, and level of proteinuria over the 6 months of the study did not significantly differ between the gemigliptin and control groups. However, biomarkers of vascular calcification, including serum bone alkaline phosphatase and kidney injury, including urine neutrophil gelatinase-associated lipocalin (NGAL)/Cr and urine liver fatty acid-binding protein (L-FABP)/Cr, were improved significantly in the gemigliptin treatment group compared with the control group. No serious adverse events were observed during the study. Conclusion. Our study showed that gemigliptin significantly improved the expression of renal tubular injury biomarkers and vascular calcification levels among patients with DKD; however, gemigliptin did not affect renal function or coronary calcification compared with those observed in the control. A larger study with a longer follow-up is essential to verify these beneficial effects. Clinical Trials. This trial is registered with ClinicalTrials.Gov Identifier NCT04705506.
1. Background
The advantage of dipeptidyl peptidase-4 (DPP-4) inhibitors is their lower risk of inducing hypoglycemia among patients with type 2 diabetes [1]. DPP-4 inhibitors impede the proteolytic enzyme DPP-4, resulting in delayed degradation of glucagon-like peptide I (GLP-1), thus improving glycemic control. Additionally, GLP-1 regulates the calcification of vascular smooth muscle cells through numerous pathways [2]. Gemigliptin is a potent DPP-4 inhibitor that has been approved for use among patients with type 2 diabetes and provides pleiotropic effects in addition to its glucose-lowering effects. It inhibits lipopolysaccharide- (LPS-) induced proinflammatory effects in vascular endothelial cells by attenuating NF-kappa B and c-Jun NH (2)-terminal kinase (JNK) signaling via an AMP-activated protein kinase- (AMPK-) dependent mechanism [3]. A recent study revealed that gemigliptin attenuates calcification of the abdominal aorta, RUNX2- and phosphate-induced Pit-1 mRNA expression, and reactive oxygen species formation [4]. Therefore, gemigliptin could alleviate vascular calcification among patients with a high risk of disease, especially diabetic kidney disease (DKD).
DPP-4 inhibitors can be used safely for patients with type 2 diabetes with renal impairment. Moreover, in an experimental model, DPP-4 inhibitors, especially gemigliptin, substantially decreased albuminuria and renal fibrosis in mice with unilateral ureteral obstruction [5] and attenuated podocyte injury in mice with diabetic nephropathy [6]. Recently, treatment with DPP-4 inhibitors attenuated kidney injury and improved acute and chronic kidney injury [7]. We therefore investigated whether gemigliptin has a similar effect among patients with DKD with a high level of vascular calcification and renal progression. We investigated the effect of gemigliptin on vascular calcification and renal injury among patients with type 2 diabetes with renal involvement.
2. Methods
2.1. Study Population
We prospectively enrolled patients from the following three hospitals in Bangkok, Thailand: Vajira Hospital, Police Hospital, and Phramongkutklao Hospital. The study implementation and protocol were approved by the institutional review board and adhered to the tenets of the Declaration of Helsinki. Informed consent was obtained from all the participants before enrollment. The inclusion criteria included patients with type 2 diabetes with CKD stages 3 to 4 (estimated glomerular filtration rate (eGFR) 15 to 60 mL/min/1.73 m²), persistent micro- or macroalbuminuria, and stable glycemic control for 12 weeks. The exclusion criteria included a history of allergy to DPP4 inhibitors, documented severe osteoporosis, concurrent infectious disease, inflammatory diseases, postkidney transplantation, and treatment with calcimimetic agents, bisphosphonates, GLP-1 receptor agonists, DPP4 inhibitors, and sodium-glucose cotransporter-2 inhibitors. Patients were withdrawn from the study when they experienced other serious side effects after inclusion, had severe hypoglycemia, or required hospitalization.
2.2. Study Design
This constituted a multicenter prospective, open-label, randomized controlled trial. Patients were randomized by the study coordinator in blocks of four; the allocation was concealed, and the patients were then divided in two groups at a ratio of 1 : 1. Group 1 received 50 mg gemigliptin daily for 6 months in addition to standard treatment, and group 2 received standard treatment for type 2 diabetes and CKD. Patients were scheduled for follow-up visits at months 2, 4, and 6, as shown in Figure 1. Diet and lifestyle modifications were advised for all participants. For 80% power at to detect a difference in biomarker levels of vascular calcification after gemigliptin treatment among patients with CKD, a total of 100 patients per group were required. Overall, 182 participants were recruited [4].
... In DOX-treated animals all the studied enzymes increased, despite that it was only significant (p ¼ 0.02) in the case of CK-MB (Table 3). Although the four enzymes studied are indicators of inflammation, LDH, CK and CK-MB are specific for inflammation and cardiac damage: in particular, CK-MB (Hrelia et al. 2002;Tokarska-Schlattner et al. 2006;Kim et al. 2017;Guven et al. 2018;Bulten et al. 2019). Its significant increase, proportional to the dose of DOX (Guven et al. 2018), confirms the cardiac damage detected by 18 F-FDG. ...
... Antioxidant enzymes are expressed much less in cardiomyocytes, compared to other organs (Hrelia et al. 2002; Torres and Simic 2012; St erba et al. 2013; De Angelis et al. 2018) which is why an imbalance occurs, that induces various mechanisms; one of them, is the activation of pro-inflammatory mediators (cytokines, chemokines, growth factors and others), which attract cells of the immune system (neutrophils and macrophages) (Mart ınez-Rodr ıguez and Carril 2013; Ghigo et al. 2016; Ertay et al. 2017; Zhang et al. 2020).The presence of neutrophils and macrophages increase the expression of GLUT1 and glycolytic enzymes such as hexokinase, which phosphorylates glucose to produce glucose-6-phosphate (Mart ınez-Rodr ıguez and Carril 2013;Ertay et al. 2017;Guven et al. 2018). Then, the glucose uptake, the main source of energy for these immune cells to carry out chemotaxis and phagocytosis, increases(Ertay et al. 2017;Kim et al. 2017), increasing 18 F-FDG uptake. c. ...
The search for methods that identify early toxicity, induced by chemotherapy, is urgent. Changes in the biodistribution of radiopharmaceuticals could give information on early toxicity. Ten-week-old CD1 male mice were divided into four groups. Two groups were administered a weekly dose of 5 mg/kg of doxorubicin hydrochloride (DOX) for 5 weeks and the control groups were administered saline solution. One week after the end of treatment, the biodistribution of ¹⁸F-FDG and ⁶⁷Ga-citrate were carried out, as was the quantification of plasma enzymes CK, CK-MB, LDH and AST. All enzymes were higher in the treated animals, but only significant (p < 0.05) in the case of CK-MB. ¹⁸F-FDG uptake increased in all organs of treated animals except retroperitoneal fat, being significant in spleen, brain, heart, liver, lung, kidney, and inguinal fat. ⁶⁷Ga-citrate had a more complex pattern. The uptake in the DOX group was higher in spleen, lung, kidney, testes, and gonadal fat, it did not change in brain, heart, and liver, and it was lower in the rest of the organs. It only showed significant differences in lung and pancreas. A thorough discussion of the possible causes that produced the change in biodistributions of both radiopharmaceuticals is included. The pilot study showed that both radiopharmaceuticals could identify early multi-organ toxicity induced by DOX. Although ¹⁸F-FDG seems to be better, ⁶⁷Ga-citrato should not be ruled out a priori. The detection of early toxicity would serve to adopt treatments that prevent its progression, thus improving patient’s quality of life.
... Meanwhile, DOX decreases the levels of major antioxidant enzymes, such as catalase (CAT) andsuperoxide dismutase (SOD) [8]. Several studies have reported that DOX induces tubulointerstitial inflammation and leads to the excessive production of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in cells [9,10]. Our previous study revealed that DOX causes NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) -mediated renal tubular injury [11]. ...
... Protein electrophoresis was utilized to separate extracted cellular lysates by employing polyacrylamide gels with different concentrations (8,10,12,15) of SDS. Proteins were electrotransferred from the gels onto polyvinylidene difluoride membranes. ...
Background and objective
Doxorubicin (DOX) is an anthracycline antitumor antibiotic widely utilized in treating various tumors. Nevertheless, the toxicity of DOX toward normal cells limits its applicability, with nephrotoxicity considered a major dose-limiting adverse effect. Apigenin (APG), a flavonoid widely distributed in natural plants, has been reported to have antioxidant, anti-inflammatory, and mild tumor-suppressive properties. In this study, we investigated the role of APG in DOX-induced nephrotoxicity and chemotherapeutic efficacy.
Methods
Male BALB/c mice were administered DOX (11.5 mg/kg) via the tail vein to establish the DOX nephropathy model. After treatment with or without APG (125, 250, and 500 mg/kg) for two weeks, urine, serum, and tissue samples were collected to evaluate proteinuria, serum albumin, serum creatinine (Scr), blood urea nitrogen (BUN), superoxide dismutase (SOD) activity, malondialdehyde (MDA), glutathione (GSH), and pathological changes. Rat renal tubular epithelial cells (NRK52E), murine podocyte cells (MPC5), and murine breast cancer cells (4T1) were utilized to verify the effect of APG on DOX-induced cell injury. An MTT assay was employed to analyze cell viability. Apoptosis was evaluated using a colorimetric TUNEL staining and cleaved caspase-3 protein analysis by western blotting. A reactive oxygen species (ROS)/superoxide (O2-) fluorescence probe was employed to determine oxidative injury. Western blotting was used to analyze nephrin, α-smooth muscle actin (α-SMA), collagen I (Col1), fibronectin (FN), and SOD2 expression. The mRNA levels of tumor necrosis factor-α (TNF-α), interleukin-18 (IL-18), IL-6, NACHT, LRR, PYD domain-containing protein 3 (NLRP3), caspase-1, and IL-1β were tested by reverse transcription-polymerase chain reaction (RT-PCR).
Results
APG ameliorated DOX-elicited renal injuries in both the glomeruli and tubules. The DOX + APG groups had much lower tissue MDA, IL-6, TNF-α, NLRP3, caspase-1, and IL-1β levels and generation of intracellular ROS, but significantly higher SOD activity and GSH levels compared to those of the DOX group. Additionally, APG attenuated DOX-induced morphological changes, loss of cellular viability, and apoptosis in NRK-52E and MPC-5 cells, but not in 4T1 cells.
Conclusion
APG has a protective role against DOX-induced nephrotoxicity, without weakening DOX cytotoxicity in malignant tumors. Thus, APG may serve as a potential protective agent against renal injury and inflammatory diseases and may be a promising candidate to attenuate renal toxicity in cancer patients treated with DOX.
... The detailed mechanisms of doxorubicin-induced renal damage remain unknown [5,6]; however, several studies implicate oxidative stress [5,[7][8][9]. In addition, El-Moselhy and El-Sheikh suggest that oxidative stress induced by doxorubicin also stimulates the release of tumor necrosis factor α (TNFα), which would further activate multiple signaling pathways, including the nuclear factor κB (NF-κB) inflammatory pathway [10]. ...
Doxorubicin is a drug that belongs to the anthracycline antibiotics. Nephrotoxicity is one of the serious side effects of doxorubicin treatment. Crocin, which is one of the most bioactive components of saffron, has antioxidant, anti-inflammatory, and antitumor effects. The current study was aimed at investigating the possible protective effects of crocin against doxorubicin-induced nephrotoxicity to elucidate the underlying mechanism of this effect. The study included four groups, six rats in each group: normal control, crocin control, doxorubicin, and crocin/doxorubicin. Doxorubicin and crocin/doxorubicin groups received intraperitoneal injections of doxorubicin (3.5 mg/kg twice weekly for 3 weeks). Rats in the crocin control group and the crocin/doxorubicin group were treated with intraperitoneal injections of crocin (100 mg/kg body weight per day) for 3 weeks. Biomarkers of kidney function and oxidative stress as well as the abundance of mRNA for nuclear factor-κβ and inducible nitric oxide synthase were evaluated. In addition, the abundance of cyclooxygenase 2 and tumor necrosis factor α immunoreactivity was evaluated. Crocin treatment had renoprotective effects manifested by significant improvement in kidney function as well as a reduction in the abundance of biomarkers of oxidative stress markers and inflammatory mediators. In conclusion, crocin has a protective effect against doxorubicin-induced nephrotoxicity in rats by serving as an antioxidant and attenuating the expression of NF-κB, iNOS, COX2, and TNFα.
... 12 In addition to the glucose-lowering effects of DPP-4 inhibitors and the tissue-protective effects of DPP-4 inhibition have been demonstrated in particular ischemia-reperfusion injury, diabetic kidney disease and CKD. Kim et al. 13 reported that gemigliptin treatment led to a reduction in apoptosis, in ammation, and oxidative stress in a murine model of adriamycin-induced nephropathy. Choi et al. 14 showed that gemigliptin attenuated cisplatin-induced renal dysfunction in mice. ...
Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control and have pleiotropic effects on kidney injury, albuminuria and vascular inflammation, especially in animal models. We plan to evaluate the effects of a potent DPP4 inhibitor (gemigliptin) on these processes in diabetic nephropathy patients.
Methods: This was a multicenter, prospective, randomized, placebo-controlled trial. A total of 201 participants were enrolled and randomly assigned to a group treated with 50 mg gemigliptin daily with standard care of diabetes mellitus for 6 months. The changes in coronary calcium score (CAC score), cardio-ankle vascular index (CAVI), estimated glomerular filtration rate (GFR), vascular calcification and tubular renal injury markers were evaluated at baseline and 6 months.
Results: In total, 182 patients completed the study. Significant reductions in hemoglobin A1C levels were observed in both groups. The changes in CAC score, CAVI, estimated GFR and proteinuria over the 6 months of the study did not significantly differ between the groups. However, biomarkers of vascular calcification, including serum bone alkaline phosphatase, and kidney injury, including urine neutrophil gelatinase-associated lipocalin (NGAL)/Cr and urine liver fatty acid-binding protein (L-FABP)/Cr, were improved significantly in the gemigliptin treatment group compared to the control group. No serious adverse event was observed during the study.
Conclusion: Our study shows that gemigliptin significantly improves renal tubular injury biomarkers and vascular calcification in patients with diabetic nephropathy; however, gemigliptin does not affect renal function or coronary calcification compared with the control. A larger and longer follow-up will be essential to determine these beneficial effects.
Clinical trials
ClinicalTrials.Gov Identifier: NCT04705506
... * P < 0.05 compared to control group; ** P < 0.05 compared DOX-treated rats. Values in parenthesis represent % change; a % change relative to control; b % change relative to DOX. their antioxidant and free radical scavenging activities (29,42,44). In the current study, the role of another medicinal plant (C. ...
Introduction: Doxorubicin (DOX), a well-known chemotherapeutic drug, has been reported to induce numerous toxic side effects including renal toxicity. This preliminary study was designed to investigate the ameliorative effects of methanolic leaf extract of Clerodendrum volubile (MECV) against DOX-induced nephrotoxicity in rats.
Methods: Thirty male rats were divided into five groups; (a) Control group: rats were given 0.9% NaCl as vehicle, (b) DOX group: a single dose of DOX (25 mg/kg; i.p.) was administered and the rats were sacrificed 4 days after DOX injection, (c-e) Methanolic extract of C. volubile (MECV)-treated DOX groups: rats were given MECV (at the doses of 125, 250 and 500 mg/kg/d), respectively for 12 consecutive days, 8 days before and 4 days after the DOX administration.
Results: DOX injection caused a significant increase (P < 0.05) in serum creatinine and urea levels. The levels of renal antioxidant parameters: glutathione peroxidase, superoxide dismutase (SOD), catalase (CAT) and reduced glutathione were significantly (P < 0.05) decreased in DOX-intoxicated rats with concomitant elevation of malondialdehyde level. Pretreatment with MECV restored antioxidant status, attenuated oxidative stress and improved kidney function markers. Pre-treatment with MECV protected renal tissues against DOX-induced nephrotoxicity.
Conclusion: The ameliorative effects of C. volubile leaves on these renal biochemical parameters may be via its antioxidant action and may serve as a novel combination agent with DOX to limit its renal damage.
... 16 For instance, it has been argued whether DPP-IV must be or must not be administered to cancer patients with diabetes, [17][18][19] whereas other studies support the oral administration of DPP-IV inhibitors in order to either enhance tumor immunotherapy 20 or to slow the growth of different tumors [21][22][23] or to suppress colorectal cancer lung metastases in mice. 24 Other studies have demonstrated their therapeutic effects on obesity, [25][26][27][28][29] neuropathy, 30 and hepatic [31][32][33][34][35][36][37] and renal [38][39][40][41][42][43][44] pathologies. Recent studies have also shown that it is possible to design DPP-IV inhibitors with dual bioactivity on other targets involved in cardiovascular diseases like ACE 45 or -adrenergic receptors. ...
The inhibition of dipeptidyl peptidase‐IV (DPP‐IV) has emerged over the last decade as one of the most effective treatments for type 2 diabetes mellitus, and consequently (a) 11 DPP‐IV inhibitors have been on the market since 2006 (three in 2015), and (b) 74 noncovalent complexes involving human DPP‐IV and drug‐like inhibitors are available at the Protein Data Bank (PDB). The present review aims to (a) explain the most important activity cliffs for DPP‐IV noncovalent inhibition according to the binding site structure of DPP‐IV, (b) explain the most important selectivity cliffs for DPP‐IV noncovalent inhibition in comparison with other related enzymes (i.e., DPP8 and DPP9), and (c) use the information deriving from this activity/selectivity cliff analysis to suggest how virtual screening protocols might be improved to favor the early identification of potent and selective DPP‐IV inhibitors in molecular databases (because they have not succeeded in identifying selective DPP‐IV inhibitors with IC50 ≤ 100 nM). All these goals are achieved with the help of available homology models for DPP8 and DPP9 and an analysis of the structure–activity studies used to develop the noncovalent inhibitors that form part of some of the complexes with human DPP‐IV available at the PDB.
