RESUMEN

Individuals suffering from diabetic polyneuropathy (DPN) experience debilitating symptoms such as pain, paranesthesia, and sensory disturbances, prompting a quest for effective treatments. Dipeptidyl-peptidase (DPP)-4 inhibitors, recognized for their potential in ameliorating DPN, have sparked interest, yet the precise mechanism underlying their neurotrophic impact on the peripheral nerve system (PNS) remains elusive. Our study delves into the neurotrophic effects of DPP-4 inhibitors, including Diprotin A, linagliptin, and sitagliptin, alongside pituitary adenylate cyclase-activating polypeptide (PACAP), Neuropeptide Y (NPY), and Stromal cell-derived factor (SDF)-1a-known DPP-4 substrates with neurotrophic properties. Utilizing primary culture dorsal root ganglia (DRG) neurons, we meticulously evaluated neurite outgrowth in response to these agents. Remarkably, all DPP-4 inhibitors and PACAP demonstrated a significant elongation of neurite length in DRG neurons (PACAP 0.1 µM: 2221 ± 466 µm, control: 1379 ± 420, p < 0.0001), underscoring their potential in nerve regeneration. Conversely, NPY and SDF-1a failed to induce neurite elongation, accentuating the unique neurotrophic properties of DPP-4 inhibition and PACAP. Our findings suggest that the upregulation of PACAP, facilitated by DPP-4 inhibition, plays a pivotal role in promoting neurite elongation within the PNS, presenting a promising avenue for the development of novel DPN therapies with enhanced neurodegenerative capabilities.

Asunto(s)

Neuropatías Diabéticas , Inhibidores de la Dipeptidil-Peptidasa IV , Ganglios Espinales , Proyección Neuronal , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Animales , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/farmacología , Proyección Neuronal/efectos de los fármacos , Neuropatías Diabéticas/tratamiento farmacológico , Neuropatías Diabéticas/metabolismo , Ratones , Neuropéptido Y/metabolismo , Neuropéptido Y/farmacología , Quimiocina CXCL12/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Linagliptina/farmacología , Dipeptidil Peptidasa 4/metabolismo , Fosfato de Sitagliptina/farmacología , Células Cultivadas , Neuritas/efectos de los fármacos , Neuritas/metabolismo , Oligopéptidos

RESUMEN

Cisplatin (CDDP) often leads to kidney impairment, limiting its effectiveness in cancer treatment. The lack of mitophagy in proximal tubules exacerbates this issue. Hence, targeting SIRT-3 and PGC1-α shows promise in mitigating CDDP-induced kidney damage. The potential renoprotective effects of linagliptin, however, remain poorly understood. This study represents the first exploration of linagliptin's impact on CDDP-induced kidney impairment in rats, emphasizing its potential role in mitophagic pathways. The experiment involved four rat groups: Group (I) received saline only, Group (II) received a single intraperitoneal injection of CDDP at 6 mg/kg. Groups (III) and (IV) received linagliptin at 6 and 10 mg/kg p.o., respectively, seven days before CDDP administration, continuing for an additional four days. Various parameters, including renal function tests, oxidative stress, TNF-α, IL-1ß, IL-6, PGC-1α, FOXO-3a, p-ERK1, and the gene expression of SIRT-3 and P62 in renal tissue, were assessed. Linagliptin improved renal function, increased antioxidant enzyme activity, and decreased IL-1ß, TNF-α, and IL-6 expression. Additionally, linagliptin significantly upregulated PGC-1α and PINK-1/Parkin-2 expression while downregulating P62 expression. Moreover, linagliptin activated FOXO-3a and SIRT-3, suggesting a potential enhancement of mitophagy. Linagliptin demonstrated a positive impact on various factors related to kidney health in the context of CDDP-induced impairment. These findings suggest a potential role for linagliptin in improving cancer treatment outcomes. Clinical trials are warranted to further investigate and validate its efficacy in a clinical setting.

Asunto(s)

Cisplatino , Linagliptina , Mitofagia , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Ubiquitina-Proteína Ligasas , Animales , Linagliptina/farmacología , Cisplatino/toxicidad , Mitofagia/efectos de los fármacos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Masculino , Ratas , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Sirtuina 3/metabolismo , Sirtuina 3/genética , Proteínas Quinasas/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Ratas Wistar , Antineoplásicos/toxicidad , Estrés Oxidativo/efectos de los fármacos , Enfermedades Renales/inducido químicamente , Enfermedades Renales/prevención & control , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Sirtuinas

Asunto(s)

Compuestos de Bencidrilo , Glucósidos , Linagliptina , Nefritis Hereditaria , Humanos , Linagliptina/uso terapéutico , Linagliptina/farmacología , Glucósidos/uso terapéutico , Glucósidos/farmacología , Compuestos de Bencidrilo/uso terapéutico , Compuestos de Bencidrilo/farmacología , Nefritis Hereditaria/tratamiento farmacológico , Masculino , Riñón/efectos de los fármacos , Riñón/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Femenino , Adulto

RESUMEN

BACKGROUND: Tacrolimus (TAC) is a frequently used immunosuppressive medication in organ transplantation. However, its nephrotoxic impact limits its long-term usage. This study aims to investigate the effect of linagliptin (Lina) on TAC-induced renal injury and its underlying mechanisms. METHODS AND RESULTS: Thirty-two Sprague Dawley rats were treated with TAC (1.5 mg/kg/day, subcutaneously) and/or Lina (5 mg/kg/day, orally) for 4 weeks. Histological examination was conducted, and serum and urinary biomarkers were measured to assess kidney function and integrity. Furthermore, ELISA, Western blot analysis and immunohistochemical assay were employed to determine signaling molecules of oxidative stress, profibrogenic, hypoxic, and apoptotic proteins. Tacrolimus caused renal dysfunction and histological deterioration evidenced by increased serum creatinine, blood urea nitrogen (BUN), urinary cystatin C, and decreased serum albumin as well as elevated tubular injury and interstitial fibrosis scores. Additionally, TAC significantly increased the expression of collagen type-1, alpha-smooth muscle actin (α-SMA), plasminogen activator inhibitor-1 (PAI-1), and transforming growth factor-beta1 (TGF-ß1) renal content. Moreover, TAC decreased the expression of nuclear factor erythroid-2-related factor2 (Nrf2), heme oxygenase 1 (HO-1), and mitochondrial superoxide dismutase (SOD2). In addition, TAC increased protein expression of hypoxia-inducible factor1-alpha (HIF-1α), connective tissue growth factor (CTGF), inducible nitric oxide synthase (iNOS), 8-hydroxy-2-deoxyguanosine (8-OHdG), as well as nitric oxide (NO), 4-hydroxynonenal, caspase-3 and Bax renal contents. Furthermore, TAC decreased Bcl-2 renal contents. The Lina administration markedly attenuated these alterations. CONCLUSION: Lina ameliorated TAC-induced kidney injury through modulation of oxidative stress, hypoxia, and apoptosis related proteins.

Asunto(s)

Lesión Renal Aguda , Riñón , Linagliptina , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Animales , Masculino , Ratas , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/tratamiento farmacológico , Factor de Crecimiento del Tejido Conjuntivo/efectos de los fármacos , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inmunosupresores/farmacología , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Linagliptina/farmacología , Factor 2 Relacionado con NF-E2/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Inhibidor 1 de Activador Plasminogénico/efectos de los fármacos , Inhibidor 1 de Activador Plasminogénico/metabolismo , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Tacrolimus/farmacología , Tacrolimus/toxicidad , Hemo-Oxigenasa 1/efectos de los fármacos , Hemo-Oxigenasa 1/metabolismo

RESUMEN

Lupus nephritis (LN) occurs in 50% of cases of systemic lupus erythematosus (SLE) and is one of the most serious complications that can occur during lupus progression. Mesangial cells (MCs) are intrinsic cells in the kidney that can regulate capillary blood flow, phagocytose apoptotic cells, and secrete vasoactive substances and growth factors. Previous studies have shown that various types of inflammatory cells can activate MCs for hyperproliferation, leading to disruption of the filtration barrier and impairment of renal function in LN. Here, we characterized the heterogeneity of kidney cells of LN mice by single-nucleus RNA sequencing (snRNA-seq) and revealed the interaction between macrophages and MCs through the CXC motif chemokine ligand 12 (CXCL12)/dipeptidyl peptidase 4 (DPP4) axis. In culture, macrophages modulated the proliferation and migration of MCs through this ligand-receptor interaction. In LN mice, treatment with linagliptin, a DPP4 inhibitor, effectively inhibited MC proliferation and reduced urinary protein levels. Together, our findings indicated that targeting the CXCL12/DPP4 axis with linagliptin treatment may serve as a novel strategy for the treatment of LN via the CXCL12/DPP4 axis.

Asunto(s)

Proliferación Celular , Quimiocina CXCL12 , Dipeptidil Peptidasa 4 , Nefritis Lúpica , Macrófagos , Células Mesangiales , Nefritis Lúpica/patología , Nefritis Lúpica/metabolismo , Animales , Dipeptidil Peptidasa 4/metabolismo , Quimiocina CXCL12/metabolismo , Células Mesangiales/metabolismo , Células Mesangiales/patología , Células Mesangiales/efectos de los fármacos , Ratones , Macrófagos/metabolismo , Proliferación Celular/efectos de los fármacos , Humanos , Femenino , Movimiento Celular/efectos de los fármacos , Comunicación Celular/efectos de los fármacos , Linagliptina/farmacología , Transducción de Señal , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Ratones Endogámicos C57BL

RESUMEN

The dipeptidyl peptidase-4 (DPP-4) inhibitors, a novel anti-diabetic medication family, are renoprotective in diabetes, but a comparable benefit in chronic non-diabetic kidney diseases is still under investigation. This study aimed to elucidate the molecular mechanisms of linagliptin's (Lina) protective role in a rat model of chronic kidney injury caused by tacrolimus (TAC) independent of blood glucose levels. Thirty-two adult male Sprague Dawley rats were equally randomized into four groups and treated daily for 28 d as follows: The control group; received olive oil (1 mL/kg/d, subcutaneously), group 2; received Lina (5 mg/kg/d, orally), group 3; received TAC (1.5 mg/kg/d, subcutaneously), group 4; received TAC plus Lina concomitantly in doses as the same previous groups. Blood and urine samples were collected to investigate renal function indices and tubular injury markers. Additionally, signaling molecules, epithelial-mesenchymal transition (EMT), and fibrotic-related proteins in kidney tissue were assessed by enzyme-linked immunosorbent assay (ELISA) and Western blot analysis, immunohistochemical and histological examinations. Tacrolimus markedly induced renal injury and fibrosis as indicated by renal dysfunction, histological damage, and deposition of extracellular matrix (ECM) proteins. It also increased transforming growth factor ß1 (TGF-ß1), Smad4, p-extracellular signal-regulated kinase (ERK)1/2/ERK1/2, and p-P38/P38 mitogen-activated protein kinase (MAPK) protein levels. These alterations were markedly attenuated by the Lina administration. Moreover, Lina significantly inhibited EMT, evidenced by inhibiting Vimentin and α-smooth muscle actin (α-SMA) and elevating E-cadherin. Furthermore, Lina diminished hypoxia-related protein levels with a subsequent reduction in Snail and Twist expressions. We concluded that Lina may protect against TAC-induced interstitial fibrosis by modulating TGF-ß1 mediated EMT via Smad-dependent and independent signaling pathways.

Asunto(s)

Transición Epitelial-Mesenquimal , Fibrosis , Linagliptina , Ratas Sprague-Dawley , Tacrolimus , Factor de Crecimiento Transformador beta1 , Animales , Linagliptina/farmacología , Linagliptina/uso terapéutico , Transición Epitelial-Mesenquimal/efectos de los fármacos , Masculino , Tacrolimus/farmacología , Factor de Crecimiento Transformador beta1/metabolismo , Transducción de Señal/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Ratas , Proteínas Smad/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Inmunosupresores/farmacología

RESUMEN

Lifestyle modifications, metformin, and linagliptin reduce the incidence of type 2 diabetes (T2D) in people with prediabetes. The gut microbiota (GM) may enhance such interventions' efficacy. We determined the effect of linagliptin/metformin (LM) vs metformin (M) on GM composition and its relationship to insulin sensitivity (IS) and pancreatic ß-cell function (Pßf) in patients with prediabetes. A cross-sectional study was conducted at different times: basal, six, and twelve months in 167 Mexican adults with prediabetes. These treatments increased the abundance of GM SCFA-producing bacteria M (Fusicatenibacter and Blautia) and LM (Roseburia, Bifidobacterium, and [Eubacterium] hallii group). We performed a mediation analysis with structural equation models (SEM). In conclusion, M and LM therapies improve insulin sensitivity and Pßf in prediabetics. GM is partially associated with these improvements since the SEM models suggest a weak association between specific bacterial genera and improvements in IS and Pßf.

Asunto(s)

Microbioma Gastrointestinal , Linagliptina , Metformina , Estado Prediabético , Humanos , Metformina/farmacología , Metformina/uso terapéutico , Microbioma Gastrointestinal/efectos de los fármacos , Estado Prediabético/tratamiento farmacológico , Estado Prediabético/microbiología , Masculino , Femenino , Persona de Mediana Edad , Estudios Transversales , Linagliptina/uso terapéutico , Linagliptina/farmacología , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/microbiología , Diabetes Mellitus Tipo 2/metabolismo , Resistencia a la Insulina , Adulto , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Anciano

RESUMEN

PURPOSE: Dipeptidyl peptidase-4 (DPP-4) inhibitors are oral hypoglycemic drugs and are used for type II diabetes. Previous studies showed that DPP-4 expression is observed in several tumor types and DPP-4 inhibitors suppress the tumor progression on murine tumor models. In this study, we evaluated the role of DPP-4 and the antitumor effect of a DPP-4 inhibitor, linagliptin, on glioblastoma (GBM). METHODS: We analyzed DPP-4 expression in glioma patients by the public database. We also analyzed DPP-4 expression in GBM cells and the murine GBM model. Then, we evaluated the cell viability, cell proliferation, cell migration, and expression of some proteins on GBM cells with linagliptin. Furthermore, we evaluated the antitumor effect of linagliptin in the murine GBM model. RESULTS: The upregulation of DPP-4 expression were observed in human GBM tissue and murine GBM model. In addition, DPP-4 expression levels were found to positively correlate with the grade of glioma patients. Linagliptin suppressed cell viability, cell proliferation, and cell migration in GBM cells. Linagliptin changed the expression of phosphorylated NF-kB, cell cycle, and cell adhesion-related proteins. Furthermore, oral administration of linagliptin decreases the tumor progression in the murine GBM model. CONCLUSION: Inhibition of DPP-4 by linagliptin showed the antitumor effect on GBM cells and the murine GBM model. The antitumor effects of linagliptin is suggested to be based on the changes in the expression of several proteins related to cell cycle and cell adhesion via the regulation of phosphorylated NF-kB. This study suggested that DPP-4 inhibitors could be a new therapeutic strategy for GBM.

Asunto(s)

Neoplasias Encefálicas , Movimiento Celular , Proliferación Celular , Dipeptidil Peptidasa 4 , Inhibidores de la Dipeptidil-Peptidasa IV , Progresión de la Enfermedad , Glioblastoma , Linagliptina , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Glioblastoma/metabolismo , Linagliptina/farmacología , Linagliptina/uso terapéutico , Animales , Humanos , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Dipeptidil Peptidasa 4/metabolismo , Ratones , Proliferación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Masculino , Supervivencia Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico

RESUMEN

Sotagliflozin is the first dual SGLT1/2 inhibitor antidiabetic drug approved by the US Food and Drug Administration for the management of heart failure. SGLT1/2 inhibition is observed to potentiate the secretion of the incretin hormone, glucagon-like peptide-1 (GLP-1). The current preclinical research sought to investigate the effect of sotagliflozin on the secretion of fat-regulating peptides such as GLP-1, glucagon and fibroblast growth factor 21 (FGF21) and their prospective association with sotagliflozin's potential beneficial effects on dyslipidaemia. During an oral fat tolerance test in mice, sotagliflozin substantially increased GLP-1 and insulin concentrations. Although sotagliflozin alone did not ameliorate postprandial lipemia, its combination with linagliptin (DPP-IV inhibitor) significantly improved lipid tolerance comparable to orlistat (lipase inhibitor). In a triton-induced hypertriglyceridemia model, sotagliflozin, along with other medications (fenofibrate, exenatide and linagliptin) reduced fat excursion; however, co-administration with linagliptin provided no extra advantage. Furthermore, sotagliflozin stimulated glucagon secretion in the alpha TC1.6 cells and healthy mice, which resulted in an increased circulating FGF21 and ß-hydroxybutyrate concentration. Finally, chronic treatment of sotagliflozin in high-fat diet (HFD)-fed obese mice resulted in reduced body weight gain, liver triglyceride, cholesterol, interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-α) levels compared with the placebo group. However, the addition of linagliptin did not provide any additional benefit. In conclusion, sotagliflozin was found to have an effect on GLP-1 and also stimulate the release of glucagon and FGF21, which are important for regulating fat metabolism. Therefore, sotagliflozin might represent a potential therapeutic approach for the treatment of diabetic dyslipidemia and steatohepatitis.

Asunto(s)

Dislipidemias , Factores de Crecimiento de Fibroblastos , Glucagón , Glicósidos , Ratones , Animales , Glucagón/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Linagliptina/farmacología , Insulina/metabolismo , Dislipidemias/tratamiento farmacológico , Glucemia/metabolismo

RESUMEN

Linagliptin is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor that indirectly elevates the glucagon-like peptide-1 (GLP-1) level. The aim of the present study was to check whether linagliptin has an influence on neurotransmission in rat brain. Rats were acutely and chronically exposed to linagliptin (10 and 20 mg/kg, intraperitoneally (i.p.)). Twenty-four hours later, the striatum and hippocampus were selected for further studies. In neurochemical experiments, using high-performance liquid chromatography with electrochemical detection (HPLC-ED), the concentrations of three major neurotransmitters-dopamine, serotonin and noradrenaline-and their metabolites were measured. The analysis of mRNA expression of dopamine (D1 and D2), serotonin (5-HT-1 and 5-HT-2) and noradrenaline (α1 and α2a) receptors was also investigated using real-time quantitative reverse transcription polymerase chain reaction (RQ-PCR) in the same brain areas. Linagliptin has the ability to influence the dopaminergic system. In the striatum, the elevation of dopamine and its metabolites was observed after repeated administration of that linagliptin, and in the hippocampus, a reduction in dopamine metabolism was demonstrated. Acute linagliptin exposure increases the serotonin level in both areas, while after chronic linagliptin administration a tendency for the mRNA expression of serotoninergic receptors (5-HT1A and 5-HT2A) to increase was observed. A single instance of exposure to linagliptin significantly modified the noradrenaline level in the striatum and intensified noradrenaline turnover in the hippocampus. The recognition of the interactions in the brain between DPP-4 inhibitors and neurotransmitters and/or receptors is a crucial step for finding novel discoveries in the pharmacology of DPP-4 inhibitors and raises hope for further applications of DPP-4 inhibitors in clinical practices.

Asunto(s)

Inhibidores de la Dipeptidil-Peptidasa IV , Linagliptina , Ratas , Animales , Linagliptina/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Serotonina , Dopamina , Norepinefrina , Dipeptidil Peptidasa 4/metabolismo , Hipocampo/metabolismo , Neurotransmisores , ARN Mensajero

RESUMEN

Uterine fibroid is the most common non-cancerous tumor with no satisfactory options for long-term pharmacological treatment. Fibroblast activation protein-α (FAP) is one of the critical enzymes that enhances the fibrosis in uterine fibroids. Through STITCH database mining, we found that dipeptidyl peptidase-4 inhibitors (DPP4i) have the potential to inhibit the activity of FAP. Both DPP4 and FAP belong to the dipeptidyl peptidase family and share a similar catalytic domain. Hence, ligands which have a binding affinity with DPP4 could also bind with FAP. Among the DPP4i, linagliptin exhibited the highest binding affinity (Dock score = -8.562 kcal/mol) with FAP. Our study uncovered that the differences in the S2 extensive-subsite residues between DPP4 and FAP could serve as a basis for designing selective inhibitors specifically targeting FAP. Furthermore, in a dynamic environment, linagliptin was able to destabilize the dimerization interface of FAP, resulting in potential inhibition of its biological activity. True to the in-silico results, linagliptin reduced the fibrotic process in estrogen and progesterone-induced fibrosis in rat uterus. Furthermore, linagliptin reduced the gene expression of transforming growth factor-ß (TGF-ß), a critical factor in collagen secretion and fibrotic process. Masson trichrome staining confirmed that the anti-fibrotic effects of linagliptin were due to its ability to reduce collagen deposition in rat uterus. Altogether, our research proposes that linagliptin has the potential to be repurposed for the treatment of uterine fibroids.

Asunto(s)

Inhibidores de la Dipeptidil-Peptidasa IV , Leiomioma , Ratas , Animales , Femenino , Linagliptina/farmacología , Linagliptina/uso terapéutico , Factor de Crecimiento Transformador beta , Dipeptidil Peptidasa 4/metabolismo , Reposicionamiento de Medicamentos , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Fibrosis , Leiomioma/tratamiento farmacológico , Colágeno , Factores de Crecimiento Transformadores

RESUMEN

Accumulating evidence suggests that dysregulation of FOXO3a plays a significant role in the progression of various malignancies, including hepatocellular carcinoma (HCC). FOXO3a inactivation, driven by oncogenic stimuli, can lead to abnormal cell growth, suppression of apoptosis, and resistance to anticancer drugs. Therefore, FOXO3a emerges as a potential molecular target for the development of innovative treatments in the era of oncology. Linagliptin (LNGTN), a DPP-4 inhibitor known for its safe profile, has exhibited noteworthy anti-inflammatory and anti-oxidative properties in previous in vivo studies. Several potential molecular mechanisms have been proposed to explain these effects. However, the capacity of LNGTN to activate FOXO3a through AMPK activation has not been investigated. In our investigation, we examined the potential repurposing of LNGTN as a hepatoprotective agent against diethylnitrosamine (DENA) intoxication. Additionally, we assessed LNGTN's impact on apoptosis and autophagy. Following a 10-week administration of DENA, the liver underwent damage marked by inflammation and early neoplastic alterations. Our study presents the first experimental evidence demonstrating that LNGTN can reinstate the aberrantly regulated FOXO3a activity by elevating the nuclear fraction of FOXO3a in comparison to the cytosolic fraction, subsequent to AMPK activation. Moreover, noteworthy inactivation of NFκB induced by LNGTN was observed. These effects culminated in the initiation of apoptosis, the activation of autophagy, and the manifestation of anti-inflammatory, antiproliferative, and antiangiogenic outcomes. These effects were concomitant with improved liver function and microstructure. In conclusion, our findings open new avenues for the development of novel therapeutic strategies targeting the AMPK/FOXO3a signaling pathway in the management of chronic liver damage.

Asunto(s)

Carcinoma Hepatocelular , Inhibidores de la Dipeptidil-Peptidasa IV , Neoplasias Hepáticas , Animales , Ratas , Linagliptina/farmacología , Proteínas Quinasas Activadas por AMP , Dietilnitrosamina/toxicidad , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/tratamiento farmacológico , Hipoglucemiantes , Inhibidores de Proteasas , Antivirales , Antiinflamatorios

RESUMEN

Extensive preclinical evidence demonstrates a causative link between insulin signaling dysfunction and the pathogenesis of Alzheimer's disease (AD), and diabetic drugs may represent a promising approach to fighting AD. However, it remains to be determined which antidiabetic drugs are more effective in preventing cognitive impairment. Thus, the present study investigated the effect of dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin on cognitive impairment in middle-aged mice by comparing it with the effect of metformin. We found that DPP-4 activity increased in the hippocampus of middle-aged mice, and DPP-4 was mainly expressed by microglia rather than astrocytes and oligodendrocytes. DPP-4 directly regulated M1/M2 microglia polarization following LPS or IL-4 stimulation, while DPP-4 inhibitor, linagliptin, suppressed M1-polarized activation and induced M2-polarized activation. Both linagliptin and metformin enhanced cognitive ability, increased hippocampal synaptic plasticity and neurogenesis, and decreased age-related oxidative stress and inflammation by regulating microglia polarization in the hippocampus of middle-aged mice. The combination of linagliptin and metformin showed a maximum protective effect compared to the individual drugs alone. Loss of macrophage inflammatory protein-1α (MIP-1α), a DPP-4 substrate, abrogated the cognitive protection and anti-inflammation effects of linagliptin. Therefore, the current investigation exhibits a potential utility for DPP-4 inhibition in attenuating microglia-mediated inflammation and preventing mild cognitive impairment (MCI) in middle-aged mice, and the effect was partly mediated by MIP-1α.

Asunto(s)

Enfermedad de Alzheimer , Disfunción Cognitiva , Inhibidores de la Dipeptidil-Peptidasa IV , Metformina , Ratones , Animales , Linagliptina/farmacología , Linagliptina/uso terapéutico , Quimiocina CCL3/farmacología , Microglía , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Disfunción Cognitiva/tratamiento farmacológico , Metformina/farmacología , Metformina/uso terapéutico , Inflamación

RESUMEN

Gastric hyperacidity and ulceration are chronic diseases characterized by repeated healing followed by re-exacerbation. The study aims to protect against gastric hyperacidity without interfering with gastric acid secretion. Pylorus ligation-induced hyperacidity is commonly utilized in the induction of gastric ulcers.Forty-two rats were distributed into seven groups (n = 6). Group I comprised sham-operated group. Group II served as pylorus-ligation group. Groups III-VII were given oral Linagliptin (LN; 3 and 6 mg/kg), L-arginine (LA; 150 and 300 mg/kg) and their combination (LN 3 + LA 150 mg/kg), respectively for 7 days. On the 8th day, groups II-VII were subjected to pylorus-ligation.Treatment of pylorus-ligated rats with LN, LA and their combination improved the gastric hyperacidity as exhibited by a marked reduction in the gastric juice volume, total and free acidities and pepsin contents with a noticeable increase in pH. Pre-treatment with LN, LA and their combination showed a marked alleviation in the gastric inflammatory indicators evidenced by reduction in the gastric levels of MCP-1and Il-1ß as well as elevation of eNOS levels versus the sham-operated group. A marked up-regulation in the gastric gene expression of PGE, EP4 and VEGF accompanied by an improvement of the histopathologic pictures/scores, and TNF-α and caspase-3 immuno-staining were also recorded.By estimating the combination-index, it can be concluded that combining LN with LA exhibited prophylactic synergistic effects in ameliorating pylorus ligated-induced hyperacidity, mainly via up-regulation of EP4 receptor and improvement of vascular endothelial damage through VEGF expression in gastric mucosa.

Asunto(s)

Píloro , Úlcera Gástrica , Ratas , Animales , Píloro/cirugía , Linagliptina/farmacología , Linagliptina/uso terapéutico , Linagliptina/metabolismo , Regulación hacia Arriba , Factor A de Crecimiento Endotelial Vascular/metabolismo , Ligadura , Mucosa Gástrica , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/etiología , Úlcera Gástrica/prevención & control , Arginina/farmacología

RESUMEN

In the current study, we established a comprehensive quantitative systems pharmacology (QSP) model using linagliptin as the model drug, where drug disposition, drug intervention on dipeptidyl peptidase-4 (DPP-4), glucose-dependent insulinotropic peptide (GIP), Glucagon-like peptide-1 (GLP-1), glucagon, glucose, and insulin are integrated together with the cross talk and feedback loops incorporated among the whole glycemic control system. In the final linagliptin QSP model, the complicated disposition of linagliptin was characterized by a 2-compartment pharmacokinetic (PK) model with an enterohepatic cycling (EHC) component as well as target-mediated drug disposition (TMDD) processes occurring in both tissues and plasma, and the inhibitory effect of linagliptin on DPP-4 was determined by the linagliptin-DPP-4 complex in the central compartment based on target occupancy principle. The integrated GIP-GLP1-glucagon-glucose-insulin system contains five indirect response models as the "skeleton" structure with 12 feedback loops incorporated within the glucose control system. Our model adequately characterized the substantial nonlinear PK of linagliptin, time course of DPP-4 inhibition, as well as the kinetics of GIP, GLP-1, glucagon, and glucose simultaneously in humans. Our model provided valuable insights on linagliptin pharmacokinetics/pharmacodynamics and complicated glucose homeostasis. Since the glucose regulation modeling framework within the QSP model is "drug-independent", our model can be easily adopted by others to evaluate the effect of other DPP-4 inhibitors on the glucose control system. In addition, our QSP model, which contains more components than other reported glucose regulation models, can potentially be used to evaluate the effect of combination antidiabetic therapy targeting different components of glucose control system.

Asunto(s)

Inhibidores de la Dipeptidil-Peptidasa IV , Humanos , Glucemia , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Polipéptido Inhibidor Gástrico/uso terapéutico , Glucagón/uso terapéutico , Péptido 1 Similar al Glucagón , Glucosa , Hipoglucemiantes/farmacocinética , Incretinas , Insulina/uso terapéutico , Linagliptina/farmacología , Linagliptina/uso terapéutico , Farmacología en Red

RESUMEN

Type 1 diabetes mellitus (T1DM) is one of the main causes of ovarian atresia, but its molecular effect on the ovaries is not fully understood. Accumulating evidence suggests that T1DM causes excessive endoplasmic reticulum (ER) stress and insufficient adaptive unfolded protein response that triggers proapoptotic signaling pathways in ovarian tissue. In addition, problems such as amenorrhea and infertility, which are frequently seen in women with T1DM, continue despite the intensification of insulin therapy and improvement of metabolic control. Therefore new, and adjunctive treatments for women with T1DM need to be explored. We aimed to examine how the use of linagliptin, which has blood sugar-lowering effects and high antioxidant activity, together with insulin affects the expression levels of proteins and genes that play a role in ER stress in type 1 diabetic mouse ovaries. Eighty-four Balb/C 6-week-old female mice were randomly divided into seven groups: control, vehicle, diabetes + insulin, diabetes + linagliptin, diabetes + linagliptin + insulin, diabetes + TUDCA, and diabetes + TUDCA + insulin. TUDCA (an inhibitor of ER stress) groups are positive control groups created to compare linagliptin groups in terms of ER stress. Linagliptin and TUDCA were given by oral gavage and 1U insulin was administered subcutaneously for 2 weeks. A significant decrease was observed in the MDA and NOX1 levels and the number of atretic follicles in the ovaries of the diabetes + linagliptin + insulin group compared to the diabetes + insulin group. The use of linagliptin and insulin increased the expression of pro-survival XBP1s transmembrane protein and decreased the expression of proapoptotic ATF4, pJNK1/2, cleaved caspase 12, and cleaved caspase 3 in mouse ovaries. Our study provides new therapeutic evidence that linagliptin administered in addition to insulin induces ER stress mechanism-dependent survival in ovaries with type 1 diabetes.

Asunto(s)

Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Ácido Tauroquenodesoxicólico , Ratones , Animales , Femenino , Humanos , Linagliptina/farmacología , Linagliptina/uso terapéutico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Insulina/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Ovario/metabolismo , Respuesta de Proteína Desplegada

RESUMEN

OBJECTIVES: The purpose of this study was to compare the effects of pioglitazone and linagliptin on glycemic control, lipid profile and high-sensitivity C-reactive protein (hs-CRP) parameters in patients with type 2 diabetes treated with metformin. METHODS: The present randomized clinical trial was conducted on 60 patients with type 2 diabetes treated with metformin in the age range of 30-60 years. The participants with informed consent were randomly assigned to receive pioglitazone or linagliptin. The first intervention group (n=30) received 30 mg of pioglitazone daily and the second intervention group (n=30) received 5 mg of linagliptin daily for 12 weeks. Fasting blood samples were taken from patients at the baseline and after 12 weeks to measure related variables. The current study was approved in Kashan University of Medical Sciences (with the code of ethics of IR.KAUMS.MEDNT.REC.1398.016), and the Iranian Registry of Clinical Trials (with the registration number of IRCT20170513033941N66). RESULTS: The linagliptin administration significantly reduced serum levels of fasting blood sugar (p=0.03), blood sugar 2 h after a meal (p=0.02), glycosylated hemoglobin (p=0.02) and hs-CRP (p=0.005) after 12 weeks compared with pioglitazone. In contrast, the pioglitazone administration significantly decreased triglyceride levels (p=0.01) and increased HDL-cholesterol (p=0.002) compared to linagliptin. In addition, the administration of both linagliptin and pioglitazone drugs had no significant effect on LDL-cholesterol, total cholesterol, systolic and diastolic blood pressure, creatinine and blood urea. CONCLUSIONS: The present study demonstrated the superiority of linagliptin over pioglitazone for glycemic control, although pioglitazone compared to linagliptin showed greater efficacy in reducing triglycerides and raising HDL-cholesterol.

Asunto(s)

Diabetes Mellitus Tipo 2 , Metformina , Tiazolidinedionas , Humanos , Adulto , Persona de Mediana Edad , Pioglitazona/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Metformina/farmacología , Metformina/uso terapéutico , Linagliptina/farmacología , Linagliptina/uso terapéutico , Proteína C-Reactiva , Glucemia/metabolismo , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Control Glucémico , Irán , Tiazolidinedionas/efectos adversos , Triglicéridos , Colesterol , HDL-Colesterol , Método Doble Ciego

RESUMEN

The aim of this study is to reveal the effects of the use of linagliptin, a DPP-4 inhibitor due to its beneficial cardiovascular effects, on endoplasmic reticulum stress (ERS) signaling, which is involved in the pathogenesis of cardiovascular complications related to type 1 diabetes. BALB/c female mice (n = 72) were divided into six groups: control, diabetes+insulin, diabetes+linagliptin, diabetes+linagliptin+insulin, diabetes+TUDCA, and diabetes+TUDCA+insulin. Immunohistochemistry and western blot method, qRT-PCR, ELISA method, and malondialdehyde (MDA) measurements were performed. Linagliptin administered to the type 1 diabetic mouse heart significantly reduced the expression levels of the total and cleaved forms of ATF6, ATF4, and p-JNK, caspase 3. Immunohistochemical and western blot analyses revealed that cleaved caspase 3 protein expression was significantly increased in the diabetes+insulin group compared to the other groups. According to ELISA findings, TUDCA was more effective in reducing NOX 1 and MDA levels than linagliptin. While linagliptin decreased the Chop mRNA level, no change was observed in the Grp78 mRNA level. Our findings showed that there was not much difference between the administration of linagliptin alone or in combination with insulin. Our study reveals that linagliptin is an effective therapeutic agent on ERS and apoptotic UPR in type 1 diabetic hearts.

Asunto(s)

Diabetes Mellitus Tipo 1 , Inhibidores de la Dipeptidil-Peptidasa IV , Ratones , Animales , Femenino , Linagliptina/farmacología , Linagliptina/uso terapéutico , Insulina , Caspasa 3 , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Respuesta de Proteína Desplegada , ARN Mensajero

RESUMEN

Purpose: This study investigated the effect of dipeptidyl peptidase-4 inhibitors (DPP-4is) on fibrosis after glaucoma filtering surgery with clinical data and an in vitro model that used transforming growth factor-ß (TGF-ß) to induce human Tenon's fibroblast (HTF) fibrosis. Methods: The medical records of 41 eyes of 35 patients with diabetes with neovascular glaucoma (NVG) who received initial trabeculectomy were retrospectively reviewed. The surgical success rate was compared between cases that received (n = 23) and did not receive (n = 18) DPP-4i treatment for diabetes. The antifibrotic effects of linagliptin (a DPP-4i) were evaluated with quantitative real-time PCR for fibrosis markers (α-smooth muscle actin, collagen Iα, and fibronectin), a scratch assay, and a collagen gel contraction assay of primary cultured HTFs treated with TGF-ß1 and linagliptin. Western blotting analysis was performed to evaluate the levels of phosphorylated Smad2 and Smad3 in the presence of linagliptin. Results: The Kaplan-Meier curve for bleb survival was higher in patients who received DPP-4is (P = 0.017, log-rank test). The in vitro experiments demonstrated that treatment with linagliptin attenuated the elevated levels of fibrosis markers induced by TGF-ß1 in HTFs. Linagliptin treatment also prevented the migration and gel contraction of HTFs. Linagliptin inhibited the phosphorylation of Smad2 and Smad3, which is the canonical pathway of TGF-ß signaling. Conclusions: The current study indicates the potential effect of DPP-4is for maintaining bleb function after glaucoma filtering surgery in patients with diabetes with NVG. Our results demonstrate that linagliptin attenuates fibrotic change in HTFs by inhibiting TGF-ß/Smad signaling.

Asunto(s)

Inhibidores de la Dipeptidil-Peptidasa IV , Glaucoma , Trabeculectomía , Humanos , Factor de Crecimiento Transformador beta1/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Inhibidores de la Dipeptidil-Peptidasa IV/metabolismo , Linagliptina/farmacología , Linagliptina/uso terapéutico , Linagliptina/metabolismo , Estudios Retrospectivos , Glaucoma/tratamiento farmacológico , Glaucoma/cirugía , Glaucoma/metabolismo , Fibrosis , Fibroblastos/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Transducción de Señal , Colágeno/metabolismo , Células Cultivadas

RESUMEN

BACKGROUND: Finding new applications for widely used current drugs is a fast and effective technique for discovering new anticancer chemicals. Osteosarcoma (OS), the most prevalent form of bone cancer, has several side effects that significantly lower patients' quality of life. This study aims to systematically examine the anti-cancer activity of linagliptin (LG) in the osteosarcoma cell line Saos-2. METHODS: MTT assays and flow cytometry were used to assess cell viability and apoptosis, respectively. qPCR array experiments were carried out to determine target gene expressions and explain the molecular mechanism of LG's action. RESULTS: Linagliptin treatment significantly decreased the viability of Saos-2 cells and hFOB1.19 cells (p < 0.001). The treatment also induced increased apoptotic effects in both Saos-2 cells (p < 0.001) and hFOB1.19 cells (p < 0.05). qPCR assays were conducted to assess cancer pathway analysis after applying specific quantities of LG to Saos-2 and hFOB1.19 cells. CONCLUSION: The findings of this study demonstrate that LG inhibits the proliferation of Saos-2 cells and induces cell death. LG supports cell death by suppressing the expression of specific genes involved in cancer pathways.

Asunto(s)

Neoplasias Óseas , Osteosarcoma , Humanos , Linagliptina/farmacología , Linagliptina/uso terapéutico , Calidad de Vida , Línea Celular Tumoral , Osteosarcoma/genética , Neoplasias Óseas/genética