RESUMEN
ETHNOPHARMACOLOGICAL PREVALENCE: Hyperglycemia in diabetes increases the generation of advanced glycation end products (AGEs) through non-enzymatic reactions. The interaction between AGEs and their receptors (RAGE) leads to oxidative and inflammatory stress, which plays a pivotal role in developing diabetic nephropathy. Syzygium cumini (SC) L. (DC.) homeopathic preparations viz. 200C, 30C, and mother tincture [MT] are used to treat diabetes. This study aimed to elucidate the regulatory effects of SC preparations (200C, 30C, and MT) on the nuclear factor erythroid 2-related factor 2 (Nrf2) - nuclear factor-κB (NF-κB) pathways and mitochondrial dysfunction in mitigating diabetic nephropathy (DN). MATERIALS AND METHODS: Streptozotocin-induced diabetic rats were treated with SC preparations (200C, 30C, MT; 1:20 dilution in distilled water; 600 µL/kg body weight) and metformin (45 mg/kg body weight) twice daily for 40 days. DN was evaluated through biochemical parameters and histological examination. Renal tissue lysates were analyzed for glycation markers. Protein and gene levels of Nrf2, NF-κB, and mitochondrial dysfunctional signaling were determined via western blotting and RT-qPCR. An immunohistochemical analysis of the kidneys was performed. In vitro, human serum albumin (HSA - 10 mg/ml) was glycated with methylglyoxal (MGO - 55 mM) in the presence of SC preparations (200C, 30C, MT) for eight days. Glycated samples (400 µg/mL) were incubated with renal cells (HEK-293) for 24 h. Further reactive oxygen species production, Nrf2 nuclear translocation, and protein or gene expression of Nrf2 and apoptosis markers were analyzed by western blotting, RT-qPCR, and flow cytometry. Molecular docking of gallic and ellagic acid with the HSA-MGO complex was performed. RESULT: In vivo experiments using streptozotocin-induced diabetic rats treated with SC preparations exhibited improved biochemical parameters, preserved kidney function, and reduced glycation adduct formation in a dose-dependent manner. Furthermore, SC preparations downregulated inflammatory mediators such as RAGE, NF-κB, vascular endothelial growth factor (VEGF), and Tumor necrosis factor α (TNF-α) while upregulating the Nrf2-dependent antioxidant and detoxification pathways. They downregulated B-cell lymphoma 2 (Bcl-2) associated X-protein (BAX), C/EBP homologous protein (CHOP), Dynamin-related protein 1 (DRP1), and upregulated BCL 2 gene expression. Notably, SC preparations facilitated nuclear translocation of Nrf2, leading to the upregulation of antioxidant enzymes and the downregulation of oxidative stress markers. Molecular docking studies revealed favorable interactions between gallic (-5.26 kcal/mol) and ellagic acid (-4.71 kcal/mol) with the HSA-MGO complex. CONCLUSION: SC preparations mitigate renal cell apoptosis and mitochondrial dysfunction through Nrf2-dependent mechanisms.
Asunto(s)
Diabetes Mellitus Experimental , Nefropatías Diabéticas , Factor 2 Relacionado con NF-E2 , Syzygium , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/metabolismo , Syzygium/química , Humanos , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Masculino , Ratas , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , FN-kappa B/metabolismo , Extractos Vegetales/farmacología , Transducción de Señal/efectos de los fármacos , Células HEK293 , Estrés Oxidativo/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Productos Finales de Glicación Avanzada/metabolismo , Estreptozocina , Ratas Wistar , Antioxidantes/farmacología , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: Accumulating experimental evidence has shown that resveratrol supplementation is effective for treating diabetic nephropathy (DN) in animal models. In this systematic review and meta-analysis, we assessed the effects and multiple mechanisms of resveratrol in animal models of DN. METHODS: Before September 2023, preclinical literature was systematically searched and screened across PubMed, Web of Science, EMBASE, and the Cochrane Library. Forty-two studies were included, and the risk of bias tool from SYRCLE was used to assess the methodological quality. Pooled overall effect sizes of the results were generated by STATA 16.0. RESULTS: The overall results provide preliminary evidence that the consumption of resveratrol can significantly reduce the mesangial index, glomerular basement membrane thickness, glomerular hypertrophy, serum creatinine, blood urea nitrogen, 24-h urinary protein, blood glucose, kidney index, total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels. In contrast, the levels of albumin and high-density lipoprotein cholesterol are significantly increased. However, resveratrol did not significantly reduce creatinine clearance or glycated hemoglobin levels. Dose-response analysis revealed that resveratrol was most effective at improving kidney function and reducing DN when administered at lower doses of ≤15 mg/kg/day or higher doses of 100-200 mg/kg/day, with significant improvements in biochemical kidney injury markers and a better effect on dysglycemia. CONCLUSIONS: The benefits of resveratrol in DN are likely due to its anti-inflammatory, antioxidant, metabolic regulatory, and autophagy-promoting effects. To confirm these findings for clinical use, further large-scale, long-term, high-quality preclinical trials are warranted to accurately assess the anti-DN effects and safety of resveratrol.
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Nefropatías Diabéticas , Resveratrol , Resveratrol/farmacología , Resveratrol/uso terapéutico , Nefropatías Diabéticas/tratamiento farmacológico , Animales , Progresión de la Enfermedad , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Antioxidantes/farmacología , Antioxidantes/uso terapéuticoAsunto(s)
Tasa de Filtración Glomerular , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Tasa de Filtración Glomerular/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Nefropatías Diabéticas/tratamiento farmacológicoRESUMEN
BACKGROUND: To systematically evaluate the efficacy and safety of Huangkui capsule (HKC) in the treatment of diabetic nephropathy (DN). METHODS: A computerized search of 8 online databases, CNKI, VIP, WANGFANG, CBM, ChiCTR, Embase, PubMed, and Cochrane Library, was conducted from the time of database construction to June 23, 2023, and randomized controlled trials of HKC for the treatment of DN were included according to the predefined screening criteria. Literature quality was evaluated with the help of Cochrane Risk of Bias Assessment Tool, and data were analyzed by STATA/MP17 and RevMan 5.3 software. RESULTS: A total of 1543 articles were retrieved, and 45 studies were finally included, all in Chinese, with a total sample size of 4297 cases, including 2168 cases in the experimental group and 2129 cases in the control group, and the quality of all the included studies was generally low. Meta-analysis showed that (1) efficacy: effective rate: [relative riskâ =â 1.24, 95% confidence interval (CI) (1.20, 1.29), Pâ <â .001], SCR: [standard mean difference (SMD)â =â -1.19, 95% CI (-1.47, -0.91), Pâ <â .001], 24 h-UTP: [SMDâ =â -1.27, 95% CI (-1.66, -0.88), Pâ <â .001]. Other renal function, glucose metabolism, lipid metabolism, and inflammatory factors related indicators improved compared with the control group. But in the outcome index of estimated glomerular filtration rate, the addition of HKC did not have an advantage over conventional treatment alone. Estimated glomerular filtration rate: [SMDâ =â -0.21, 95% CI (-0.80, 0.39), Pâ =â .50]. (2) Safety: There was no statistical significance in the incidence of adverse reactions between the study group with the addition of HKC and the control group. CONCLUSION: The clinical efficacy and safety of DN treated with the combination of HKC is better than that of conventional western medicine alone, but to better evaluate the efficacy and safety of HKC as an adjunctive intervention for DN, more rigorously designed large-sample, multicenter randomized controlled trials are needed to provide evidence support in the future.
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Nefropatías Diabéticas , Medicamentos Herbarios Chinos , Humanos , Nefropatías Diabéticas/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Medicamentos Herbarios Chinos/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
Hu antigen R (HuR) plays a key role in regulating genes critical to the pathogenesis of diabetic nephropathy (DN). This study investigates the therapeutic potential of niclosamide (NCS) as an HuR inhibitor in DN. Uninephrectomized mice were assigned to four groups: normal control; untreated db/db mice terminated at 14 and 22 weeks, respectively; and db/db mice treated with NCS (20 mg/kg daily via i.p.) from weeks 18 to 22. Increased HuR expression was observed in diabetic kidneys from db/db mice, which was mitigated by NCS treatment. Untreated db/db mice exhibited obesity, progressive hyperglycemia, albuminuria, kidney hypertrophy and glomerular mesangial matrix expansion, increased renal production of fibronectin and a-smooth muscle actin, and decreased glomerular WT-1+-podocytes and nephrin expression. NCS treatment did not affect mouse body weight, but reduced blood glucose and HbA1c levels and halted the DN progression observed in untreated db/db mice. Renal production of inflammatory and oxidative stress markers (NF-κBp65, TNF-a, MCP-1) and urine MDA levels increased during disease progression in db/db mice but were halted by NCS treatment. Additionally, the Wnt1-signaling-pathway downstream factor, Wisp1, was identified as a key downstream mediator of HuR-dependent action and found to be markedly increased in db/db mouse kidneys, which was normalized by NCS treatment. These findings suggest that inhibition of HuR with NCS is therapeutic for DN by improving hyperglycemia, renal inflammation, and oxidative stress. The reduction in renal Wisp1 expression also contributes to its renoprotective effects. This study supports the potential of repurposing HuR inhibitors as a novel therapy for DN.
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Nefropatías Diabéticas , Reposicionamiento de Medicamentos , Proteína 1 Similar a ELAV , Niclosamida , Animales , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/metabolismo , Ratones , Proteína 1 Similar a ELAV/metabolismo , Proteína 1 Similar a ELAV/genética , Masculino , Niclosamida/farmacología , Niclosamida/uso terapéutico , Riñón/metabolismo , Riñón/patología , Riñón/efectos de los fármacos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Glucemia/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Diabetes mellitus has emerged as a pressing global concern, with a notable increase in recent years. Despite advancements in treatment, existing medications struggle to halt the progression of diabetes and its associated complications. Increasing evidence underscores inflammation as a significant driver in the onset of diabetes mellitus. Therefore, perspectives on new therapies must consider shifting focus from metabolic stress to inflammation. High mobility group box (HMGB-1), a nuclear protein regulating gene expression, gained attention as an endogenous danger signal capable of sparking inflammatory responses upon release into the extracellular environment in the late 1990s. PURPOSE: Given the parallels between inflammatory responses and type 2 diabetes (T2D) development, this review paper explores HMGB-1's potential involvement in onset and progression of diabetes complications. Specifically, we will review and update the understanding of HMGB-1 and its inflammatory pathways in insulin resistance, diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy. CONCLUSIONS: HMGB-1 and its receptors i.e. receptor for advanced glycation end-products (RAGE) and toll-like receptors (TLRs) present promising targets for antidiabetic interventions. Ongoing and future projects in this realm hold promise for innovative approaches targeting HMGB-1-mediated inflammation to ameliorate diabetes and its complications.
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Proteína HMGB1 , Hipoglucemiantes , Receptor para Productos Finales de Glicación Avanzada , Transducción de Señal , Humanos , Proteína HMGB1/metabolismo , Proteína HMGB1/antagonistas & inhibidores , Animales , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Receptor para Productos Finales de Glicación Avanzada/antagonistas & inhibidores , Hipoglucemiantes/uso terapéutico , Mediadores de Inflamación/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Antiinflamatorios/uso terapéutico , Terapia Molecular Dirigida , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/tratamiento farmacológico , Resistencia a la Insulina , Receptores Toll-Like/metabolismo , Retinopatía Diabética/metabolismo , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/etiología , Retinopatía Diabética/prevención & control , Neuropatías Diabéticas/metabolismo , Neuropatías Diabéticas/etiología , Neuropatías Diabéticas/tratamiento farmacológico , Complicaciones de la Diabetes/metabolismo , Complicaciones de la Diabetes/tratamiento farmacológicoRESUMEN
Diabetic nephropathy (DN) is one of the most important comorbidities of diabetic patients, which places large physiological and economic burdens on patients. Safflower yellow, a natural pigment extracted from the petals of safflower, has been put into adjuvant therapy. Databases including Chinese National Knowledge Infrastructure (CNKI), Wanfang Database, MEDLINE and etc. will be searched for relevant articles. A meta-analysis was carried out to assess the efficacy and safety of safflower yellow adjuvant to conventional treatment regimen using mean differences (MD) and rate ratios (RR). A cost-effectiveness analysis was also conducted based on the result of meta-analysis. Finally, 28 articles involving 2251 patients were included in meta-analysis. The results showed that compared with conventional treatment, the fasting blood-glucose (FBG) [MD = 0.40], urinary albumin ejection rate (UAER) within 24 h [MD = 48.16], serum creatinine (Scr) [MD = 9.63], blood urea nitrogen (BUN) [MD = 1.73] were significantly lower and the clinical efficacy [RR = 1.28] was more remarkable in safflower yellow adjuvant to conventional treatment group. Our analysis suggested that safflower yellow adjuvant to conventional treatment regimen not only had better clinical efficacy but more cost-effective than conventional treatment regimen.
Asunto(s)
Chalcona , Nefropatías Diabéticas , Humanos , Nefropatías Diabéticas/tratamiento farmacológico , Chalcona/análogos & derivados , Chalcona/uso terapéutico , Análisis Costo-Beneficio , Resultado del Tratamiento , Glucemia/metabolismo , Creatinina/sangreRESUMEN
AIMS: Finerenone has been approved for treating diabetic kidney disease (DKD) with reducing cardiorenal risk. Real-world data on finerenone treatment for the management of DKD are presently lacking. This study aimed to investigate the effect of finerenone on the renal parameters of the Chinese DKD population in the real-world medical setting for the first time, especially in combination with renin-angiotensin system inhibitors (RASi) and sodium-glucose cotransporter 2 inhibitors (SGLT2i). METHODS: Forty-two DKD patients were selected and completed a 6-month finerenone treatment. Renal parameters and adverse effects were collected at every visit. RESULTS: The median urine albumin-to-creatinine ratio (UACR) was 1426.11 (755.42, 3638.23) mg/g. Among them, the proportion of patients with a UACR of 300-5000 mg/g was 76.2%, and the proportion of patients with a UACR of >5000 mg/g was 14.3%. The median estimated glomerular filtration rate (eGFR) was 54.50 (34.16, 81.73) mL/min/1.73 m2. Finerenone decreased the UACR significantly throughout the study period (p < .05). The maximal decline of UACR at month 6 was 73%. Moreover, the proportion of patients with a 30% or greater reduction in UACR was 68.42% in month 6. There was a smaller decline (9-11%) in the eGFR after initiating finerenone (p > .05). One patient each discontinued finerenone due to hyperkalemia (2.4%) and acute kidney injury (2.4%). No patient reported hypotension, breast pain, and gynecomastia. CONCLUSIONS: This study from China first demonstrated finerenone decreased UACR with manageable safety in real-world DKD treatment. A triple regimen of RASi, SGLT2i, and finerenone may be a promising treatment strategy for lowering albuminuria and reducing hyperkalemia risk in advanced DKD patients.
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Nefropatías Diabéticas , Tasa de Filtración Glomerular , Naftiridinas , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Masculino , Femenino , Nefropatías Diabéticas/tratamiento farmacológico , China , Persona de Mediana Edad , Anciano , Naftiridinas/uso terapéutico , Naftiridinas/efectos adversos , Tasa de Filtración Glomerular/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Albuminuria/tratamiento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Antagonistas de Receptores de Mineralocorticoides/efectos adversos , Creatinina/sangre , Creatinina/orina , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Sistema Renina-Angiotensina/efectos de los fármacos , Resultado del TratamientoRESUMEN
In addition to optimal glycemic control and management of other factors aggravating the pathology (hypertension, dyslipidemia, -obesity), the cornerstone of treatment of diabetic kidney disease (DKD) includes blockers of the renin-angiotensin system, sodium-glucose cotransporter 2 inhibitors or nonsteroidal antagonists of the mineralocorticoid receptor (finerenone). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are recommended in the treatment of high-risk patients with type 2 diabetes (T2DM) to reduce cardiovascular (CV) risk. Data from CV studies indicate a nephroprotective effect of certain GLP-1 RAs in T2DM patients with DKD. The FLOW study published in May 2024, analyzing the impact of semaglutide vs placebo on renal events as primary outcome, confirms this renal protection of GLP-1 RAs.
Outre le contrôle glycémique et la prise en charge d'autres facteurs d'aggravation de la pathologie, la pierre angulaire du traitement de la maladie rénale diabétique (MRD) comprend les bloqueurs du système rénine-angiotensine, les inhibiteurs du cotransporteur sodium-glucose de type 2 ou encore la finérénone (antagoniste de l'aldostérone). Les agonistes du récepteur du glucagon-like peptide-1 (ARGLP-1) sont recommandés dans le traitement des patients avec un diabète de type 2 (DT2) à haut risque afin de réduire le risque cardiovasculaire (CV). Les données provenant des études CV indiquent un effet néphroprotecteur de certains ARGLP-1 chez les patients DT2 avec MRD. L'étude FLOW, publiée fin mai 2024 et analysant l'impact du sémaglutide sur les événements rénaux comme critère principal, confirme cette protection rénale des ARGLP-1.
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Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Receptor del Péptido 1 Similar al Glucagón , Humanos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Nefropatías Diabéticas/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Péptidos Similares al Glucagón/uso terapéutico , Péptidos Similares al Glucagón/farmacología , Enfermedades Cardiovasculares/prevención & control , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/fisiología , Agonistas Receptor de Péptidos Similares al GlucagónRESUMEN
Inflammation and fibrosis play important roles in diabetic kidney disease (DKD). Previous studies have shown that glucagon-like peptide-1 receptor (GLP-1R) agonists had renal protective effects. However, the mechanisms are not clear. The present study explored the effect of liraglutide (LR), a GLP-1R agonist, on the downregulation of glomerular inflammation and fibrosis in DKD by regulating the Toll-like receptor (TLR)4/myeloid differentiation marker 88 (MyD88)/nuclear factor κB (NF-κB) signaling pathway in mesangial cells (MCs). In vitro, rat MCs were cultured in high glucose (HG). We found that liraglutide treatment significantly reduced the HG-mediated activation of the TLR4/MYD88/NF-κB signaling pathway, extracellular matrix (ECM)-related proteins, and inflammatory factors. A combination of TLR4 inhibitor (TAK242) and liraglutide did not synergistically inhibit inflammatory factors and ECM proteins. Furthermore, in the presence of TLR4 siRNA, liraglutide significantly blunted HG-induced expression of fibronectin protein and inflammatory factors. Importantly, TLR4 selective agonist LPS or TLR4 overexpression eliminated the improvement effects of liraglutide on the HG-induced response. In vivo, administration of liraglutide for 8 wk significantly improved the glomerular damage in streptozotocin-induced diabetic mice and reduced the expression of TLR4/MYD88/NF-κB signaling proteins, ECM protein, and inflammatory factors in renal cortex. TLR4-/- diabetic mice showed significant amelioration in urine protein excretion rate, glomerular pathological damage, inflammation, and fibrosis. Liraglutide attenuated glomerular hypertrophy, renal fibrosis, and inflammatory response in TLR4-/- diabetic mice. Taken together, our findings suggest that TLR4/MYD88/NF-κB signaling is involved in the regulation of inflammatory response and ECM protein proliferation in DKD. Liraglutide alleviates inflammation and fibrosis by downregulating the TLR4/MYD88/NF-κB signaling pathway in MCs.NEW & NOTEWORTHY Liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), has renoprotective effect in diabetic kidney disease (DKD). In DKD, TLR4/MYD88/NF-κB signaling is involved in the regulation of inflammatory responses and extracellular matrix (ECM) protein proliferation. Liraglutide attenuates renal inflammation and overexpression of ECM proteins by inhibiting TLR4/MYD88/NF-κB signaling pathway. Therefore, we have identified a new mechanism that contributes to the renal protection of GLP-1RA, thus helping to design innovative treatment strategies for diabetic patients with various complications.
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Diabetes Mellitus Experimental , Nefropatías Diabéticas , Fibrosis , Liraglutida , Factor 88 de Diferenciación Mieloide , FN-kappa B , Transducción de Señal , Receptor Toll-Like 4 , Animales , Liraglutida/farmacología , Liraglutida/uso terapéutico , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/patología , Nefropatías Diabéticas/metabolismo , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Masculino , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/complicaciones , Ratones , Ratones Endogámicos C57BL , Ratas , Regulación hacia Abajo/efectos de los fármacos , Ratas Sprague-Dawley , Células Mesangiales/efectos de los fármacos , Células Mesangiales/metabolismo , Células Mesangiales/patología , Ratones Noqueados , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéuticoRESUMEN
The attenuation of glomerular hyperfiltration is posited to be a principal mechanism underlying the kidney protective effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors in diabetic kidney disease. Notably, the impact of SGLT2 inhibitors on kidney hemodynamic function has been posited to vary between type 1 and type 2 diabetes. The study by Wada et al. documents that in an animal model of type 2 diabetes, SGLT2 inhibitors mitigate glomerular hyperfiltration predominantly through afferent arteriolar constriction, a process mediated by the adenosine/A1 receptor pathway. This observation is consistent with mechanisms identified in type 1 diabetes, arguing for similar methods in type 1 and 2 diabetes.
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Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Hemodinámica , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/fisiopatología , Diabetes Mellitus Tipo 2/complicaciones , Humanos , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/fisiopatología , Nefropatías Diabéticas/etiología , Ratas , Hemodinámica/efectos de los fármacos , Tasa de Filtración Glomerular/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/fisiopatología , Riñón/irrigación sanguínea , Transportador 2 de Sodio-Glucosa/metabolismo , Arteriolas/efectos de los fármacos , Arteriolas/fisiopatología , Investigación Biomédica TraslacionalRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Linggui-Zhugan (LGZG) comprises four herbs and is a classic formula in traditional Chinese medicine. There is strong clinical evidence of its pleiotropic effects in the prevention of diabetes and its related complications. Although several classes of drugs are currently available for clinical management of diabetic kidney disease (DKD), tight glycemic and/or hypertension control may not prevent disease progression. This study evaluated the therapeutic effect of the ethnopharmacological agent LGZG on DKD. AIM OF THE STUDY: This study aimed to investigate the effects of LGZG formula with standard quality control on experimental DKD and its related metabolic disorders in animal model. Meanwhile, the present study aimed to investigate regulatory effects of LGZG on renal proteinase 3 (PR3) to reveal mechanisms underlying renoprotective benefits of LGZG. MATERIALS AND METHODS: LGZG decoction was fingerprinted by high-performance liquid chromatography for quality control. An experimental model of DKD was induced in C57 BL/6J mice by a combination of high-fat diet feeding, uninephrectomy, and intraperitoneal injection of streptozocin. The LGZG decoction was administrated by daily oral gavage. RESULTS: Treatment with LGZG formula significantly attenuated DKD-like traits (including severe albuminuria, mesangial matrix expansion, and podocyte loss) and metabolic dysfunction (disordered body composition and dyslipidemia) in mice. RNA sequencing data revealed a close association of LGZG treatment with marked modulation of signaling pathways related to podocyte injury and cell apoptosis. Mechanistically, LGZG suppressed the DKD-triggered increase in renal PR3 and podocyte apoptosis. In-vitro incubation of mouse immortalized podocytes with LGZG-medicated serum attenuated PR3-mediated apoptosis. CONCLUSION: Our data demonstrated that the LGZG formula protected against DKD in mice and was closely associated with its inhibitory effects on PR3-mediated podocyte apoptosis.
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Apoptosis , Nefropatías Diabéticas , Medicamentos Herbarios Chinos , Ratones Endogámicos C57BL , Podocitos , Animales , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/prevención & control , Nefropatías Diabéticas/patología , Podocitos/efectos de los fármacos , Podocitos/patología , Apoptosis/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Masculino , Ratones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/complicacionesRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Fufang Zhenzhu Tiaozhi (FTZ) capsule is a hospital preparation of a patented traditional Chinese medicine compound. FTZ has been clinically used for nearly 13 years in the treatment of diabetes and glycolipid metabolic diseases. With the significant benefits of SGLT2 inhibitor in patients with diabetic kidney disease (DKD), it provides a research avenue to explore the mechanism of FTZ in treating this disease based on glycolysis pathway. AIM OF THE STUDY: To explore the pharmacological characteristics of FTZ in DKD mice and its impact on the glycolysis pathway. MATERIALS AND METHODS: We induced a DKD model in C57BL/6 mice by injection of streptozotocin (STZ) combined with long-term high-fat diet. We administered three doses of FTZ for 12 weeks of treatment. Kidney function, blood lipid levels, glucose tolerance, and key glycolytic enzymes were evaluated. Renal pathological changes were observed using HE, MASSON, and PAS staining. The potential targets of the active ingredients of FTZ in the glycolysis pathway were predicted using network pharmacology and molecular docking. Validation was performed using immunohistochemistry and Western blotting. RESULTS: FTZ effectively reduces blood glucose, total cholesterol, triglyceride, low density lipoprotein cholesterol, 24 h proteinuria, serum creatinine, blood urea nitrogen, and increases urinary glucose levels. Glucose tolerance and renal pathological changes were significantly improved by FTZ treatment. Pinusolidic acid, a component of FTZ, shows good binding affinity with three active pockets of SGLT2. WB and immunohistochemistry revealed that FTZ significantly inhibits the expression of SGLT2 and its glycolytic related proteins (GLUT2/PKM2/HK2). Hexokinase, pyruvate kinase, and lactate dehydrogenase in the kidney were also significantly inhibited by FTZ in a dose-dependent manner. CONCLUSION: FTZ may alleviate the progression of DKD by inhibiting the activation of the SGLT2/glycolytic pathway. Our study provides new insights into the clinical application of FTZ in DKD.
Asunto(s)
Diabetes Mellitus Experimental , Nefropatías Diabéticas , Medicamentos Herbarios Chinos , Glucólisis , Ratones Endogámicos C57BL , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Transportador 2 de Sodio-Glucosa , Animales , Nefropatías Diabéticas/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/uso terapéutico , Masculino , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Glucólisis/efectos de los fármacos , Transportador 2 de Sodio-Glucosa/metabolismo , Ratones , Glucemia/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Simulación del Acoplamiento Molecular , Estreptozocina , Cápsulas , Dieta Alta en Grasa/efectos adversosRESUMEN
Diabetic nephropathy, a leading cause of end-stage renal disease, accounts for significant morbidity and mortality. It is characterized by microinflammation in the glomeruli and myofibroblast activation in the tubulointerstitium. Salvia miltiorrhiza Bunge, a traditional Chinese medicine, is shown to possess anti-inflammatory and anti-fibrotic properties, implying its renal-protective potential. This study investigates which type of component can reduce the damage caused by diabetic nephropathy in a single setting. The ethyl acetate (EtOAc) layer was demonstrated to provoke peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ activities in renal mesangial cells by dual luciferase reporter assay. In a high glucose (HG)-cultured mesangial cell model, the EtOAc layer substantially inhibited HG-induced elevations of interleukin-1ß, transforming growth factor-ß1 (TGF-ß1), and fibronectin, whereas down-regulated PPAR-γ was restored. In addition, among the extracts of S. miltiorrhiza, the EtOAc layer effectively mitigated TGF-ß1-stimulated myofibroblast activation. The EtOAc layer also showed a potent ability to attenuate renal hypertrophy, proteinuria, and fibrotic severity by repressing diabetes-induced proinflammatory factor, extracellular matrix accumulation, and PPAR-γ reduction in the STZ-induced diabetes mouse model. Our findings, both in vitro and in vivo, indicate the potential of the EtOAc layer from S. miltiorrhiza for future drug development targeting diabetic nephropathy.
Asunto(s)
Acetatos , Diabetes Mellitus Experimental , Nefropatías Diabéticas , Medicamentos Herbarios Chinos , Fibrosis , PPAR gamma , Salvia miltiorrhiza , Salvia miltiorrhiza/química , Animales , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Ratones , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Medicamentos Herbarios Chinos/química , PPAR gamma/metabolismo , Acetatos/química , Acetatos/farmacología , Masculino , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Células Mesangiales/efectos de los fármacos , Células Mesangiales/metabolismo , Fibronectinas/metabolismo , Ratones Endogámicos C57BL , PPAR alfa/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/química , Glucosa/metabolismoRESUMEN
The aim of this study was to assess the effect of triterpenoids on the development of diabetic nephropathy in an experimental model of diabetes mellitus. For this purpose, a destoned and dehydrated olive oil (DDOO) was used, comparing its effects to a destoned olive oil (DOO). DDOO had a higher triterpenoid content than DOO but an equal content of alcoholic polyphenols. Four study groups (n = 10 animals/group) were formed: healthy rats, diabetic control rats (DRs), and DRs treated orally with 0.5 mL/kg/day of DOO or DDOO for two months. DRs showed impaired renal function (proteinuria, increased serum creatinine, decreased renal creatinine clearance) and morphology (glomerular volume and glomerulosclerosis). These alterations correlated with increased systemic and renal tissue oxidative stress and decreased prostacyclin production. DDOO administration significantly reduced all variables of renal damage, as well as systemic and renal oxidative stress, to a greater extent than the effect produced by DOO. In conclusion, triterpenoid-rich olive oil may prevent kidney damage in experimental diabetes mellitus.
Asunto(s)
Diabetes Mellitus Experimental , Nefropatías Diabéticas , Aceite de Oliva , Estrés Oxidativo , Triterpenos , Aceite de Oliva/farmacología , Aceite de Oliva/química , Animales , Triterpenos/farmacología , Nefropatías Diabéticas/tratamiento farmacológico , Masculino , Diabetes Mellitus Experimental/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Ratas , Riñón/efectos de los fármacos , Riñón/metabolismo , Ratas Wistar , Insuficiencia Renal Crónica/tratamiento farmacológico , Modelos Animales de Enfermedad , Creatinina/sangreRESUMEN
BACKGROUND: Diabetic kidney disease (DKD) is associated with a higher risk of cardiovascular disease (CVD). Pentoxifylline (PTF), a nonselective phosphodiesterase inhibitor with anti-inflammatory, antiproliferative, and antifibrotic actions, has demonstrated renal benefits in both clinical trials and meta-analyses. The present work aimed to study the effects of PTF on the progression of subclinical atherosclerosis (SA) in a population of patients with diabetes and moderate to severe chronic kidney disease (CKD). METHODS: In this open-label, randomized controlled, prospective single-center pilot study the evolution of carotid intima-media thickness (CIMT) and ankle-brachial index (ABI) were determined in 102 patients with type 2 diabetes mellitus and CKD assigned to PTF, aspirin or control groups during 18 months. We also determined the variations in the levels of inflammatory markers and Klotho (KL), a protein involved in maintaining cardiovascular health, and their relationship with the progression of SA. RESULTS: Patients treated with PTF presented a better evolution of CIMT, increased KL mRNA levels in peripheral blood cells (PBCs) and reduced the inflammatory state. The progression of CIMT values was inversely related to variations in KL both in serum and mRNA expression levels in PBCs. Multiple regression analysis demonstrated that PTF treatment and variations in mRNA KL expression in PBCs, together with changes in HDL, were significant determinants for the progression of CIMT (adjusted R2 = 0.24, P < 0.001) independently of traditional risk factors. Moreover, both variables constituted protective factors against a worst progression of CIMT [OR: 0.103 (P = 0.001) and 0.001 (P = 0.005), respectively]. CONCLUSIONS: PTF reduced SA progression assessed by CIMT variation, a beneficial effect related to KL gene expression in PBCs. TRIAL REGISTRATION: The study protocol code is PTF-AA-TR-2009 and the trial was registered on the European Union Drug Regulating Authorities Clinical Trials (EudraCT #2009-016595-77). The validation date was 2010-03-09.
Asunto(s)
Grosor Intima-Media Carotídeo , Diabetes Mellitus Tipo 2 , Progresión de la Enfermedad , Pentoxifilina , Insuficiencia Renal Crónica , Humanos , Proyectos Piloto , Masculino , Persona de Mediana Edad , Pentoxifilina/uso terapéutico , Femenino , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/complicaciones , Estudios Prospectivos , Anciano , Resultado del Tratamiento , Factores de Tiempo , Nefropatías Diabéticas/diagnóstico , Nefropatías Diabéticas/tratamiento farmacológico , Glucuronidasa/sangre , Glucuronidasa/genética , Biomarcadores/sangre , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/tratamiento farmacológico , Enfermedades Asintomáticas , Mediadores de Inflamación/sangre , Inhibidores de Fosfodiesterasa/uso terapéutico , Antiinflamatorios/uso terapéutico , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/diagnóstico , OsteocalcinaRESUMEN
BACKGROUND: Diabetic nephropathy (DN) is a major contributor to chronic kidney disease. This study aims to identify immune biomarkers and potential therapeutic drugs in DN. METHODS: We analyzed two DN microarray datasets (GSE96804 and GSE30528) for differentially expressed genes (DEGs) using the Limma package, overlapping them with immune-related genes from ImmPort and InnateDB. LASSO regression, SVM-RFE, and random forest analysis identified four hub genes (EGF, PLTP, RGS2, PTGDS) as proficient predictors of DN. The model achieved an AUC of 0.995 and was validated on GSE142025. Single-cell RNA data (GSE183276) revealed increased hub gene expression in epithelial cells. CIBERSORT analysis showed differences in immune cell proportions between DN patients and controls, with the hub genes correlating positively with neutrophil infiltration. Molecular docking identified potential drugs: cysteamine, eltrombopag, and DMSO. And qPCR and western blot assays were used to confirm the expressions of the four hub genes. RESULTS: Analysis found 95 and 88 distinctively expressed immune genes in the two DN datasets, with 14 consistently differentially expressed immune-related genes. After machine learning algorithms, EGF, PLTP, RGS2, PTGDS were identified as the immune-related hub genes associated with DN. In addition, the mRNA and protein levels of them were obviously elevated in HK-2 cells treated with glucose for 24 h, as well as their mRNA expressions in kidney tissues of mice with DN. CONCLUSION: This study identified 4 hub immune-related genes (EGF, PLTP, RGS2, PTGDS), as well as their expression profiles and the correlation with immune cell infiltration in DN.
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Nefropatías Diabéticas , Aprendizaje Automático , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/tratamiento farmacológico , Humanos , Animales , Ratones , Proteínas RGS/genética , Perfilación de la Expresión Génica , Simulación del Acoplamiento Molecular , AlgoritmosRESUMEN
Diabetic kidney disease (DKD) is a devastating kidney disease and lacks effective therapeutic interventions. The present study was aimed to determine whether reconstituted high-density lipoprotein (rHDL) ameliorated renal injury in eNOS-/- dbdb mice, a mouse model of DKD. Three groups of mice, wild type C57BLKS/J (non-diabetes), eNOS-/- dbdb (diabetes), and eNOS-/- dbdb treated with rHDL (diabetes+rHDL) with both males and females were used. The rHDL nanoparticles were administered to eNOS-/- dbdb mice at Week 16 at 5 µg/g body weight in ~100 µL of saline solution twice per week for 4 weeks via retroorbital injection. We found that rHDL treatment significantly blunted progression of albuminuria and GFR decline observed in DKD mice. Histological examinations showed that the rHDLs significantly alleviated glomerular injury and renal fibrosis, and inhibited podocyte loss. Western blots and immunohistochemical examinations showed that increased protein abundances of fibronectin and collagen IV in the renal cortex of eNOS-/- dbdb mice were significantly reduced by the rHDLs. Taken together, the present study suggests a renoprotective effect of rHDLs on DKD.
Asunto(s)
Nefropatías Diabéticas , Lipoproteínas HDL , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa de Tipo III , Animales , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/patología , Ratones , Masculino , Óxido Nítrico Sintasa de Tipo III/metabolismo , Lipoproteínas HDL/farmacología , Femenino , Ratones Noqueados , Riñón/patología , Riñón/metabolismo , Riñón/efectos de los fármacos , Albuminuria , Fibronectinas/metabolismo , Fibronectinas/genética , Fibrosis , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológicoRESUMEN
Diabetic nephropathy (DN) is one of the leading clinical causes of end-stage renal failure. The classical aldose reductase (AR) inhibitor epalrestat shows beneficial effect on renal dysfunction induced by DN, with metabolic profile and molecular mechanisms remains to be investigated further. In the current study, integrated untargeted metabolomics, network pharmacology and molecular dynamics approaches were applied to explore the therapeutic mechanisms of epalrestat against DN. Firstly, untargeted serum and urine metabolomics analysis based on UPLC-Q-TOF-MS was performed, revealed that epalrestat could regulate the metabolic disorders of amino acids metabolism, arachidonic acid metabolism, pyrimidine metabolism and citrate cycle metabolism pathways after DN. Subsequently, metabolomics-based network analysis was carried out to predict potential active targets of epalrestat, mainly involving AGE-RAGE signaling pathway, TNF signaling pathway and HIF-1 signaling pathway. Moreover, a 100 ns molecular dynamics approach was employed to validate the interactions between epalrestat and the core targets, showing that epalrestat could form remarkable tight binding with GLUT1 and NFκB than it with AR. Surface-plasmon resonance assay further verified epalrestat could bind GLUT1 and NFκB proteins specifically. Overall, integrated system network analysis not only demonstrated that epalrestat could attenuate DN induced metabolic disorders and renal injuries, but also revealed that it could interact with multi-targets to play a synergistic regulatory role in the treatment of DN.
Asunto(s)
Nefropatías Diabéticas , Metabolómica , Simulación de Dinámica Molecular , Rodanina , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/metabolismo , Animales , Masculino , Rodanina/análogos & derivados , Rodanina/uso terapéutico , Rodanina/farmacología , Tiazolidinas/farmacología , Tiazolidinas/uso terapéutico , Humanos , Aldehído Reductasa/metabolismo , Aldehído Reductasa/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Transportador de Glucosa de Tipo 1/metabolismo , FN-kappa B/metabolismo , Farmacología en Red , RatasRESUMEN
PURPOSE: To assess the effect of Amorphophallus campanulatus tuber (Ac) extract in the protection of diabetic nephropathy in streptozotocin (STZ) induced diabetic nephropathy (DN) rat model. METHODS: Diabetes was induced with STZ (60 mg/kg, i.p.), and DN was confirmed after six weeks of STZ administration with the estimation of kidney function test. Further rats were treated with Ac 250 and 500 mg/kg p.o. for next four week. Oxidative stress and level of inflammatory cytokines were estimated in the kidney tissue of DN rats. Histopathology of kidney tissue was performed using hematoxylin and eosin staining. RESULTS: There was improvement in the body weight of Ac treated groups than DN group of rats. Blood glucose level was observed to be reduced in Ac treated groups than DN group on 42nd and 70th day of protocol. Treatment with Ac ameliorated the altered level of kidney function tests (creatinine and BUN), enzymes of liver function (aspartate aminotransferase and alanine aminotransferase), and lipid profile in the serum of DN rats. Oxidative stress parameters (malondialdehyde and reactive oxygen species enhances and reduction in the level of glutathione and superoxide dismutase) and inflammatory cytokines such as interleukin-6, tumour necrosis factor-α, and monocyte chemoattractant protein-1 reduces in the tissue of Ac treated group than DN group. Treatment with Ac also attenuates the altered histopathological changes in the kidney tissue of DN rats. CONCLUSIONS: The report suggests that Ac protects renal injury in DN rats by regulating inflammatory cytokines and oxidative stress.