Syzygium cumini (L.) skeels mitigate diabetic nephropathy by regulating Nrf2 pathway and mitocyhondrial dysfunction: In vitro and in vivo studies.

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.

Effectiveness and safety of finerenone in diabetic kidney disease patients: a real-world observational study from China.

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.

Repurposing Niclosamide to Modulate Renal RNA-Binding Protein HuR for the Treatment of Diabetic Nephropathy in db/db Mice.

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.

4-Octyl itaconate attenuates renal tubular injury in db/db mice by activating Nrf2 and promoting PGC-1α-mediated mitochondrial biogenesis.

Objectives: The aim of this study was to investigate the mechanism of itaconate's potential effect in diabetic kidney disease.Methods: Renal immune responsive gene 1 (IRG1) levels were measured in db/db mice and streptozotocin (STZ) + high-fat diet (HFD)-induced diabetic mice. Irg1 knockout mice were generated. db/db mice were treated with 4-octyl itaconate (4-OI, 50 mg/kg), a derivative of itaconate, for 4 weeks. Renal function and morphological changes were investigated. Ultrastructural alterations were determined by transmission electron microscopy.Results: Renal IRG1 levels were reduced in two diabetic models. STZ+HFD-treated Irg1 knockout mice exhibited aggravated renal tubular injury and worsened renal function. Treatment with 4-OI lowered urinary albumin-to-creatinine ratio and blood urea nitrogen levels, and restored renal histological changes in db/db mice. It improved mitochondrial damage, increased expressions of peroxisome-proliferator-activated receptor γ coactivator-1α (PGC-1α) and mitochondrial transcription factor A (TFAM) in the renal cortex of db/db mice. These were confirmed in vitro; 4-OI improved high glucose-induced abnormal mitochondrial morphology and TFAM expression in HK-2 cells, effects that were inhibited by PGC-1α silencing. Moreover, 4-OI reduced the number of apoptotic cells in the renal cortex of db/db mice. Further study showed that 4-OI increased renal Nrf2 expression and decreased oxidative stress levels in db/db mice. In HK-2 cells, 4-OI decreased high glucose-induced mitochondrial ROS production, which was reversed by Nrf2 silencing. Nrf2 depletion also inhibited 4-OI-mediated regulation of PGC-1α, TFAM, and mitochondrial apoptotic protein expressions.Conclusions: 4-OI attenuates renal tubular injury in db/db mice by activating Nrf2 and promoting PGC-1α-mediated mitochondrial biogenesis.

The role of high mobility group box-1 on the development of diabetes complications: A plausible pharmacological target.

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.

Comparative study of safflower yellow adjuvant to conventional treatment regimen and conventional treatment regimen on diabetic nephropathy.

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.

Efficacy and safety of Huangkui capsule for diabetic nephropathy: A systematic review and meta-analysis.

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 risk = 1.24, 95% confidence interval (CI) (1.20, 1.29), P < .001], SCR: [standard mean difference (SMD) = -1.19, 95% CI (-1.47, -0.91), P < .001], 24 h-UTP: [SMD = -1.27, 95% CI (-1.66, -0.88), P < .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: [SMD = -0.21, 95% CI (-0.80, 0.39), P = .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.

Resveratrol delays the progression of diabetic nephropathy through multiple pathways: A dose-response meta-analysis based on animal models.

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.

Predicting prospective therapeutic targets of Bombyx batryticatus for managing diabetic kidney disease through network pharmacology analysis.

We conducted network pharmacology and molecular docking analyses, and executed in vitro experiments to assess the mechanisms and prospective targets associated with the bioactive components of Bombyx batryticatus in the treatment of diabetic kidney disease (DKD). The bioactive components and potential targets of B batryticatus were sourced from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. Using 5 disease databases, we conducted a comprehensive screening of potential disease targets specifically associated with DKD. Common targets shared between the bioactive components and disease targets were identified through the use of the R package, and subsequently, a protein-protein interaction network was established using data from the STRING database. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses pertaining to the identified common targets were conducted using the Database for Annotation, Visualization, and Integrated Discovery. Molecular docking simulations involving the bioactive components and their corresponding targets were modeled through AutoDock Vina and Pymol. Finally, to corroborate and validate these findings, experimental assays at the cellular level were conducted. Six bioactive compounds and 142 associated targets were identified for B batryticatus. Among the 796 disease targets associated with DKD, 56 targets were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed the involvement of these shared targets in diverse biological processes and signaling pathways, notably the PI3K-Akt signaling pathway. Molecular docking analyses indicated a favorable binding interaction between quercetin, the principal bioactive compound in B batryticatus, and RAC-alpha serine/threonine-protein kinase. Subsequently, in vitro experiments substantiated the inhibitory effect of quercetin on the phosphorylation level of PI3K and Akt. The present study provides theoretical evidence for a comprehensive exploration of the mechanisms and molecular targets by which B batryticatus imparts protective effects against DKD.

[GLP-1 receptor agonists : impact on diabetic kidney disease]. / Agonistes des récepteurs du GLP-1 : ­impact sur la maladie rénale diabétique.

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.

The Role of Marein During Endothelial-Mesenchymal Transition in Diabetic Kidney Disease / Rol de la Mareína Durante la Transición Endotelial-Mesenquimatosa en la Enfermedad Renal Diabética

SUMMARY: Marein is a flavonoid compound that reduces blood glucose and lipids and has a protective effect in diabetes. However, the effect and mechanism(s) of marein on renal endothelial-mesenchymal transition in diabetic kidney disease (DKD) have not been elucidated. In this study, single-cell sequencing data on DKD were analyzed using a bioinformation method, and the data underwent reduced dimension clustering. It was found that endothelial cells could be divided into five subclusters. The developmental sequence of the subclusters was 0, 1, 4, 2, and 3, of which subcluster 3 had the most interstitial phenotype.The expression of mesenchymal marker protein:Vimentin(VIM), Fibronectin(FN1), and fibroblast growth factor receptor 1 (FGFR1) increased with the conversion of subclusters. In db/db mice aged 13-14 weeks, which develop DKD complications after 8-12 weeks of age, marein reduced blood levels of glucose, creatinine, and urea nitrogen, improved structural damage in kidney tissue, and reduced collagen deposition and the expression of FN1 and VIM. Marein also up-regulated autophagy marker:Light chain 3II/I(LC3II/I) and decreased FGFR1 expression in renal tissue. In an endothelial-mesenchymal transition model, a high glucose level induced a phenotypic change in human umbilical vein endothelial cells. Marein decreased endothelial cell migration, improved endothelial cell morphology, and decreased the expression of VIM and FN1. The use of the FGFR1 inhibitor, AZD4547, and autophagy inhibitor, 3-Methyladenine(3-MA), further demonstrated the inhibitory effect of marein on high glucose-induced endothelial-mesenchymal transition by reducing FGFR1 expression and up-regulating the autophagy marker protein, LC3II/I. In conclusion, this study suggests that marein has a protective effect on renal endothelial- mesenchymal transition in DKD, which may be mediated by inducing autophagy and down-regulating FGFR1 expression.

La mareína es un compuesto flavonoide que reduce la glucosa y los lípidos en sangre y tiene un efecto protector en la diabetes. Sin embargo, no se han dilucidado el efecto y los mecanismos de la mareína sobre la transición endotelial- mesenquimatosa renal en la enfermedad renal diabética (ERD). En este estudio, los datos de secuenciación unicelular sobre DKD se analizaron utilizando un método de bioinformación y los datos se sometieron a una agrupación de dimensiones reducidas. Se descubrió que las células endoteliales podían dividirse en cinco subgrupos. La secuencia de desarrollo de los subgrupos fue 0, 1, 4, 2 y 3, de los cuales el subgrupo 3 tenía el fenotipo más intersticial. La expresión de la proteína marcadora mesenquimatosa: vimentina (VIM), fibronectina (FN1) y receptor del factor de crecimiento de fibroblastos. 1 (FGFR1) aumentó con la conversión de subgrupos. En ratones db/db de 13 a 14 semanas de edad, que desarrollan complicaciones de DKD después de las 8 a 12 semanas de edad, la mareína redujo los niveles sanguíneos de glucosa, creatinina y nitrógeno ureico, mejoró el daño estructural en el tejido renal y redujo la deposición y expresión de colágeno de FN1 y VIM. Marein también aumentó el marcador de autofagia: Cadena ligera 3II/I (LC3II/I) y disminuyó la expresión de FGFR1 en el tejido renal. En un modelo de transición endotelial-mesenquimal, un nivel alto de glucosa indujo un cambio fenotípico en las células endoteliales de la vena umbilical humana. Marein disminuyó la migración de células endoteliales, mejoró la morfología de las células endoteliales y disminuyó la expresión de VIM y FN1. El uso del inhibidor de FGFR1, AZD4547, y del inhibidor de la autofagia, 3-metiladenina (3-MA), demostró aún más el efecto inhibidor de la mareína en la transición endotelial-mesenquimal inducida por niveles altos de glucosa al reducir la expresión de FGFR1 y regular positivamente la proteína marcadora de autofagia. , LC3II/I. En conclusión, este estudio sugiere que la mareína tiene un efecto protector sobre la transición endotelial-mesenquimatosa renal en la ERC, que puede estar mediada por la inducción de autofagia y la regulación negativa de la expresión de FGFR1.

GLP-1 RAs and SGLT2-Is to Lower Glucose and Reduce the Risk of Cardiovascular and Diabetic Kidney Disease.

The landscape of diabetes management has changed, such that the goal of pharmacotherapy extends beyond glucose-lowering to prioritize risk reduction of cardiovascular disease and diabetic kidney disease. Two newer classes of medications, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2-Is), have become first line therapies for many patients with type 2 diabetes to reduce cardiovascular and renal complications of type 2 diabetes. This review article will describe the mechanism of action, evidence for cardiovascular and kidney outcomes, contraindications, adverse effects, and risk mitigation strategies for the GLP-1 RA and SGLT2-I drug classes. In addition, we will provide a practical approach for primary care clinicians to prescribe, adjust, and combine these medication classes, while considering patient preference, tolerability, comorbidities, cost, and availability.

Comparing the effects of biguanides and dipeptidyl peptidase-4 inhibitors on cardio-cerebrovascular outcomes, nephropathy, retinopathy, neuropathy, and treatment costs in diabetic patients.

BACKGROUND: Western guidelines often recommend biguanides as the first-line treatment for diabetes. However, dipeptidyl peptidase-4 (DPP-4) inhibitors, alongside biguanides, are increasingly used as the first-line therapy for type 2 diabetes (T2DM) in Japan. However, there have been few studies comparing the effectiveness of biguanides and DPP-4 inhibitors with respect to diabetes-related complications and cardio-cerebrovascular events over the long term, as well as the costs associated. OBJECTIVE: We aimed to compare the outcomes of patients with T2DM who initiate treatment with a biguanide versus a DPP-4 inhibitor and the long-term costs associated. METHODS: We performed a cohort study between 2012 and 2021 using a new-user design and the Shizuoka Kokuho database. Patients were included if they were diagnosed with T2DM. The primary outcome was the incidence of cardio-cerebrovascular events or mortality from the initial month of treatment; and the secondary outcomes were the incidences of related complications (nephropathy, renal failure, retinopathy, and peripheral neuropathy) and the daily cost of the drugs used. Individuals who had experienced prior events during the preceding year were excluded, and events within 6 months of the start of the study period were censored. Propensity score matching was performed to compare between two groups. RESULTS: The matched 1:5 cohort comprised 529 and 2,116 patients who were initially treated with a biguanide or a DPP-4 inhibitor, respectively. Although there were no significant differences in the incidence of cardio-cerebrovascular events or mortality and T2DM-related complications between the two groups (p = 0.139 and p = 0.595), daily biguanide administration was significantly cheaper (mean daily cost for biguanides, 61.1 JPY; for DPP-4 inhibitors, 122.7 JPY; p<0.001). CONCLUSION: In patients with T2DM who initiate pharmacotherapy, there were no differences in the long-term incidences of cardio-cerebrovascular events or complications associated with biguanide or DPP-4 use, but the former was less costly.

Efficacy and safety of polyethylene glycol loxenatide in treating mild-to-moderate diabetic kidney disease in type 2 diabetes patients: a randomized, open-label, clinical trial.

Objective: This study aimed to evaluate the efficacy and safety of polyethylene glycol loxenatide (PEG-Loxe) compared to those of dapagliflozin in patients with mild-to-moderate diabetic kidney disease (DKD), a prevalent microvascular complication of type 2 diabetes mellitus (T2DM). The study is set against the backdrop of increasing global diabetes incidence and the need for effective DKD management. Methods: This study constituted a single-center, randomized, open-label, clinical trial. The trial included patients with mild-to-moderate DKD and suboptimal glycemic control. Eligible participants were randomly allocated to one of the two groups for treatment with either PEG-Loxe or dapagliflozin. The primary endpoint was the change in UACR from baseline at 24 weeks. Results: Overall, 106 patients were randomized and 80 patients completed the study. Following 24 weeks of treatment, the PEG-Loxe group exhibited a mean percent change in baseline UACR of -29.3% (95% confidence interval [CI]: -34.8, -23.7), compared to that of -31.8% in the dapagliflozin group (95% CI: -34.8, -23.7). Both PEG-Loxe and dapagliflozin showed similar efficacy in reducing UACR, with no significant difference between the groups (p = 0.336). The HbA1c levels decreased by -1.30% (95% CI: -1.43, -1.18) in the PEG-Loxe group and by -1.29% (95% CI: -1.42, -1.17) in the dapagliflozin group (p = 0.905). The TG levels decreased by -0.56 mmol/L (95% CI: -0.71, -0.42) in the PEG-Loxe group and -0.33 mmol/L (95% CI: -0.48, -0.19) in the dapagliflozin group (p = 0.023). Differences in TC, HDL-C, LDL-C, SBP, and DBP levels between the groups were not statistically significant (all p > 0.05). Safety profiles were consistent with previous findings, with gastrointestinal adverse events being more common in the PEG-Loxe group. Conclusions: PEG-Loxe is as effective as dapagliflozin in improving urine protein levels in patients with mild-to-moderate DKD and offers superior benefits in improving lipid profiles. These findings support the use of PEG-Loxe in DKD management, contributing to evidence-based treatment options. Clinical Trial Registration: www.chictr.org.cn, identifier ChiCTR2300070919.

Exploring the role of NLRP3 inflammasome in diabetic nephropathy and the advancements in herbal therapeutics.

Diabetic nephropathy (DN), a prevalent complication of diabetes mellitus (DM), is clinically marked by progressive proteinuria and a decline in glomerular filtration rate. The etiology and pathogenesis of DN encompass a spectrum of factors, including hemodynamic alterations, inflammation, and oxidative stress, yet remain incompletely understood. The NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, a critical component of the body's innate immunity, plays a pivotal role in the pathophysiology of DN by promoting the release of inflammatory cytokines, thus contributing to the progression of this chronic inflammatory condition. Recent studies highlight the involvement of the NLRP3 inflammasome in the renal pathology associated with DN. This article delves into the activation pathways of the NLRP3 inflammasome and its pathogenic implications in DN. Additionally, it reviews the therapeutic potential of traditional Chinese medicine (TCM) in modulating the NLRP3 inflammasome, aiming to provide comprehensive insights into the pathogenesis of DN and the current advancements in TCM interventions targeting NLRP3 inflammatory vesicles. Such insights are expected to lay the groundwork for further exploration into TCM-based treatments for DN.

Mitochondrial dysfunction in diabetic nephropathy: insights and therapeutic avenues from traditional Chinese medicine.

Diabetic nephropathy (DN) is a microvascular complication of diabetes mellitus. The progressive damage to glomeruli, tubules, and interstitium in the kidneys can lead to the development of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Most of the energy we need comes from mitochondria. Mitochondria are best known as the sites for production of respiratory ATP and are essential for eukaryotic life. The pathogenesis of DN involves a variety of factors, such as altered haemodynamics, oxidative stress, and inflammation, and studies from animal models suggest that mitochondrial dysfunction plays an important role in the development of DN. Traditional Chinese medicine (TCM) has a history of more than 2,500 years and has rich experience and remarkable efficacy in the treatment of DN. Recent studies have found that TCM may have great potential in regulating mitochondrial dysfunction in the treatment of DN. This review will elucidate the main causes of mitochondrial dysfunction and the relationship with DN, and explore in depth the potential mechanisms of TCM to protect the kidney by improving mitochondrial dysfunction. Current pharmacological treatments for patients with DN do not prevent the inevitable progression to ESRD. With the rich variety of Chinese herbs, TCM is expected to be the most promising candidate for the treatment of DN as we continue to learn more about the mechanisms of DN and incorporate the current advances in extraction techniques.

Identification of key immune-related genes and potential therapeutic drugs in diabetic nephropathy based on machine learning algorithms.

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.

Pentoxifylline ameliorates subclinical atherosclerosis progression in patients with type 2 diabetes and chronic kidney disease: a randomized pilot trial.

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.

Reconstituted HDL ameliorated renal injury of diabetic kidney disease in mice.

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.