Diabetic nephropathy, a serious diabetes complication, lacks effective treatments. Traditional Chinese medicine Zuogui Pill (ZGP) and Yougui Pill (YGP) have a definite clinical adjunctive effect on diabetic nephropathy. Given their similar compositions, studying their shared mechanisms could provide novel perspectives into discovering therapeutic targets for diabetic nephropathy. Extraction of ZGP (EZP) and YGP (EYP) was prepared by in vitro digestion. EZP and EYP inhibited the gene expression of FN1 and MMP9 in a renal fibrosis cell model. A transcriptional regulatory network revealed EZP and EYP have similar mechanisms, with HIF1A as a key transcription factor. In an insulin resistance cell model, EZP and EYP led to the decrease in glucose consumption. A transcriptional regulatory network suggested that EZP and EYP have different regulatory panels, but PPARA was the common transcriptional factor. CA9 and PDK1, the downstream genes of HIF1A, and PDK4, the downstream gene of PPARA, were activated by both EZP and EYP, which showed the potential new targets of diabetic nephropathy. A total of 42 compounds from EZP and EYP were screened as the potential mediators of HIF1AN and EGLN1, interacted proteins and common targets of HIF1A. A total of 8 compounds, including verbascoside, were screened as the potential PPARA agonists based on molecular docking. Verbascoside improved the decrease in glucose consumption. The study clarified the mechanism of the ZGP and YGP by regulating the transcriptional regulatory network of HIF1A and PPARA and provided new ideas for the discovery of potential targets for the treatment of diabetic nephropathy and the development of natural nutrients.

Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer and poses a significant global health challenge due to its rising incidence and associated mortality. Recent advancements in understanding the cytosolic DNA sensing, the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway have illuminated its critical role in the immune response to HCC. This narrative review deciphers the multifaceted involvement of cGAS-STING in HCC, mainly its function in detecting cytosolic DNA and initiating type I interferon (IFN-I) responses, which are pivotal for antitumor immunity. This immune response is crucial for combating pathogens and can play a role in tumor surveillance. In the context of HCC, the tumor microenvironment (TME) can exhibit immune resistance, which complicates the effectiveness of therapies like immune checkpoint blockade. However, activation of the cGAS-STING pathway has been shown to stimulate antitumor immune responses, enhancing the activity of dendritic cells and cytotoxic T lymphocytes. There is ongoing research into STING agonists as a treatment strategy for HCC, with some studies indicating promising results in prolonging survival and enhancing the immune response against tumors. By summarizing current knowledge and identifying research gaps, this review aims to provide a comprehensive overview of cGAS-STING signaling in HCC and its future directions, emphasizing its potential as a therapeutic target in the fight against HCC. Understanding these mechanisms could pave the way for innovative immunotherapeutic approaches that enhance the efficacy of existing treatments and improve patient prognosis.

MicroRNAs (miRNAs) exhibit essential effects on the occurrence and progress of diabetes mellitus (DM) and DM complications. However, the detailed role of miRNAs in diabetic ketoacidosis (DKA) is rarely reported.

The present work focused on the role of miR-214-3p on DKA and the detailed mechanisms.

First, macrophages were isolated from the venous blood of DKA patients, and ELISA was employed to determine the serum levels of inflammatory factors, serum macrophage numbers by flow cytometry, and macrophage miR-214-3p expression levels determined through PCR.. Subsequently, miR-214-3p was overexpressed in macrophages to detect macrophage proliferation, apoptosis, pyroptosis and inflammatory factor secretion. A dual luciferase reporter was used to analyze the downstream targets of miR-214-3p. Finally, macrophages overexpressing miR-214-3p were co-cultured with Human Umbilical Vein Endothelial Cells (HUVECs) to detect the effects of HUVECs proliferation, apoptosis, and angiogenesis and barrier function.

First, there is an elevation in serum inflammatory factors and a reduction in miR-214-3p levels in serum macrophages among DKA patients, and overexpression of miR-214-3p by macrophages promotes their proliferation, inhibits their pyroptosis, and reduces the secretion of inflammatory factors. In addition, Receptor-interacting protein kinase 1 (RIPK1) was predicted to be a target of miR-214-3p. Finally, co-culture of macrophages overexpressing miR-214-3p with HUVECs promoted HUVECs proliferation, inhibited apoptosis, and facilitated the tube-forming ability and repaired the barrier function of HUVECs.

MiR-214-3p targets RIPK1 and regulates vascular endothelial function in diabetic ketoacidosis, suggesting that miR-214-3p has the potential to be a novel marker for the treatment of DKA.

Diabetic nephropathy (DN) is the most common complication of type II diabetes. Rehmannia glutinosa (RG) is a traditional Chinese herb widely used in the treatment of diabetes and its complications; however, its pharmacological mechanism of action is incomplete. This study analysed the chemical composition of RG water extract (RGW) and RG ethanol extract (RGE) using UPLC-Q-TOF/MS and evaluated the in vitro activity. Moreover, a Sprague-Dawley rat model of DN was constructed using a high-fat diet and intraperitoneal injections of streptozotocin, followed by treatment of DN rats with RGW (250 and 500 mg/kg body weight) and observation of treatment effects. Water extraction of RG was efficient and had high total flavonoid and total polysaccharide contents. We identified 60 and 62 compounds from RGW and RGE, respectively, with RGW having the highest catalpol content. The combined antioxidant capacity of RGW was stronger than that of RGE, and the in vitro inhibitory activities of α-amylase and α-glucosidase were relatively high. RGW treatment resulted in reduced food intake, water intake, and blood glucose levels in DN rats. Furthermore, RGW improved blood lipid levels, improved kidney and hepatic function and antioxidant capacity, reduced inflammatory factor levels in DN rats, and improved pathological damage to the kidneys. The mRNA and protein expression levels of toll-like receptor 4, myeloid differentiation factor 88, and nuclear factor-κB p65 were all decreased. These results indicate that RG may be a potential therapeutic agent for improving DN, and its mechanism of action has been further clarified.

Major depression, type 2 diabetes, and essential (primary) hypertension are chronic medical and psychiatric disorders that have traditionally affected primarily adults and middle-aged individuals. However, recent decades have witnessed an increasing prevalence of these conditions among children and adolescents. For diseases that typically require prolonged exposure to risk factors to emerge in childhood and adolescence, the amount of exposure to a single risk factor would have to be exceptionally high. We advance the alternative hypothesis of multiple factors acting synergistically. Biological mechanisms underlying the response to ongoing (chronic) stress are logical candidates for being a shared pathway. In the context of persistent and synergistic psychological, social, and economic pressures, unremitting stress can lead to such disease outcomes, exerting a direct influence on the emergence of chronic disorders, and it can also contribute to obesity. Depression follows the same trajectory; therefore, we should examine it as an entity whose consequences are directly reflected in behavioral outcomes, including (over-) eating. Other contributing pathways include chronic sleep deprivation, epigenetic modifications, telomere shortening, the physical environment, pathogens, and the microbiome. We introduce here the concept of the Chronic inflammation, Obesity, Insulin resistance/type 2 diabetes, and Depressive Syndromes (COIDS) noxious quartet of pro-inflammatory stress outcomes, as an increasingly common pathophysiologic state, representing a distinct presentation of type 2 allostatic overload, with direct implications for the current chronic disease epidemic. The compounded effects of a pro-inflammatory state that is fueled by four different and co-existing sources may contribute to explain the emergence of chronic diseases of adulthood and middle age in the young. PPARγ might represent a potential translational therapeutic target for those with COIDS. We propose that highly adverse environments sustain sufficient chronic stress to bring about in the young diseases that had been previously confined to adults.

Empagliflozin was associated with a slower progression of kidney disease. We aimed to investigate the effect of empagliflozin on alleviating complement over-activation in DKD.

100 patients with DKD were recruited, they were divided into three groups: group I, 50 patients type 2 diabetes mellitus (T2DM) with chronic kidney disease (CKD) stage I-II; group II, 50 patients T2DM with CKD stage III; and the control group, which included 50 healthy, age-matched volunteers. Groups I and II received empagliflozin, while Group III received a placebo. Before and after six months on empagliflozin, the patients in both groups underwent tests for serum creatinine, uric acid, fasting blood glucose (FBG), glycated hemoglobin (HbA1c) urine albumin/creatinine ratio, and blood levels of human complement fragment 4d (C4d).

The optimal cut off value of C4d was ascertained to be 17.55 U/L with a sensitivity of about 68 % and specificity of about 68 %. There were statistically significant differences in Group I after empagliflozin treatment (p < 0.001): HbA1c (6.5 to 5.7), C4d (16 to 7U/l). Whereas serum creatinine (1.9 to 1.7mg/dl), HbA1c (9.9 to 6.7 %), urine albumin/creatinine ratio (115 to 49), and C4d (18 to 11U/l) were significantly improved in Group II after using empagliflozin (p < 0.001). There was a negative correlation between C4d levels and the percent change in uric acid (r -0.647-, p < 0.001).

Empagliflozin may have a beneficial effect on mitigating complement over-activation in DKD. Further research is needed to confirm our findings.

Aim: Spinal cord injury (SCI) is a catastrophic injury characterized by oxidative stress. Glutathione peroxidase 3 (GPx3) is an antioxidant enzyme that protects against immune responses in various diseases. However, the effects of GPx3 in SCI remains unclear. This study aimed to investigate the role of GPx3 in SCI and its underlying mechanisms. Results: We injected adeno-associated viruses to overexpress GPx3 in mice. Primary microglia and BV2 cells were used as in vitro models. We knocked down or overexpressed GPx3 in BV2 cells. Additionally, BV2 cells transfected with siIRAK4 were used to perform rescue experiments. A series of histological and molecular biological analyses were used to explore the role of GPx3 in SCI. Overexpression of GPx3 inhibited oxidative stress in mice, improving functional recovery after SCI. Similarly, LPS+ATP stimulation decreased GPx3 expression in microglia. Silencing of GPx3 elevated the generation of reactive oxygen species, increased the expression of IRAK4 and pro-inflammatory factors, and promoted pyroptosis in microglia. However, overexpression of GPx3 reversed these results. Moreover, silencing of IRAK4 alleviated these phenomena, which were upregulated by GPx3 deficiency. Innovation and Conclusion: Our results demonstrated that GPx3 plays a critical role in SCI by inhibiting microglial pyroptosis via the IRAK4/ROS/NLRP3 signaling pathway. Antioxid. Redox Signal. 42, 711-729.

Immune imbalance is the core pathophysiological mechanism of the deterioration of β-cell function driven by lipid metabolism disorders. Toll-like receptor 4 (TLR4) inflammatory signaling is a key pathway that mediates lipotoxic injury in β-cells, but the underlying mechanism needs to be further elucidated. Transmembrane protein 24 (TMEM24) is a key transporter that regulates pulsatile insulin secretion, but its pathophysiology in lipotoxicity remains unclear. In this study, we investigate whether TLR4-mediated lipotoxicity is affected by the inhibition of TMEM24 expression. The PPI network shows that TLR4 is associated with both insulin secretion and ER stress proteins in islets from obese rats. Using in vitro lipotoxic β-cell models, we found that TMEM24 is the target signal of palmitic acid (PA)-induced insulin secretion impairment in islet β-cells, and TLR4 plays a mediating role in this process. Mechanistically, TLR4 mediates lipotoxicity by binding to TMEM24 and downregulating its protein expression to suppress PI3K/AKT signaling, leading to β-cell dysfunction. TLR4 knockout ameliorates islet function impairment through TMEM24/PI3K/AKT signaling in HFD-induced obese rats. Taken together, our results show that TLR4 mediates lipotoxicity in islet β-cells by inhibiting the TMEM24/PI3K/AKT pathway, and the mechanism of TLR4-mediated lipotoxicity is elucidated from the perspective of insulin vesicular secretion.

Diabetic nephropathy (DN) is a severe microvascular complication of diabetes with a complex pathogenesis.

Recent studies were reviewed to explore the role of gut microbiota and its metabolites in DN development.

Dysbiosis of gut bacteria contributes to pathological changes such as glomerular sclerosis and renal tubule injury. Microbial metabolites are involved in DN through immune and inflammatory pathways.

Understanding the relationship between gut microbiota, its metabolites, and DN may offer potential implications for DN diagnosis, prevention, and treatment. Translating this knowledge into clinical practice presents challenges and opportunities.

Diabetes mellitus, a global health challenge, influences millions worldwide by leading to severe complications and premature death. A key factor in its pathogenesis is immune cell dysfunction, which aggravates both type 1 and type 2 diabetes. The important role that immune cell dysregulation plays in the emergence of diabetes complications is investigated in this research. It highlights the manner in which diabetes compromises the immune system's adaptive as well as innate responses. Key defects in innate immunity include impaired pathogen recognition, and dysfunctional behavior of macrophages, neutrophils, and natural killer (NK) cells. Additionally, the complement system is dysregulated, and cytokine production is altered, affecting overall immune signaling. The study investigates the dysfunction of several T and B cell subsets, such as CD4+ T cells, CD8+ T cells, regulatory T cells, and B cells, in relation to adaptive immunity. These dysfunctions collectively contribute to chronic inflammation, reduced pathogen clearance, and increased susceptibility to infections, ultimately exacerbating diabetes complications. Developing targeted therapies to reduce diabetes complications and enhance patient outcomes requires an understanding of these mechanisms.

Earlier studies have implicated a crucial link between diabetic nephropathy (DN) and the gut microbiota (GM) by considering the gut-kidney axis; however, the specific cause-and-effect connections between these processes remain unclear.

To compare changes in the GM between DN patients and control subjects, a review of observational studies was performed. The examination focused on the phylum, family, genus, and species/genus categories. To delve deeper into the cause-effect relationship, instrumental variables for 211 GM taxa (9 phyla, 16 classes, 20 orders, 35 families, and 131 genera), which were eligible for the mbQTL (microbial quantitative trait locus) mapping analysis, were collected from the Genome Wide Association Study (GWAS). A Mendelian randomization investigation was then conducted to gauge their impact on DN susceptibility using data from the European Bioinformatics Institute (EBI) and the FinnGen consortium. The European Bioinformatics Institute data included 1032 DN patients and 451,248 controls, while the FinnGen consortium data consisted of 3283 DN patients and 210,463 controls. Two-sample Mendelian randomization (TSMR) was utilized to determine the link between the GM and DN. The primary method for analysis was the inverse variance weighted (IVW) approach. Moreover, a reverse Mendelian randomization analysis was carried out, and the findings were validated through sensitivity assessments.

This review examined 11 observational studies that satisfied the inclusion and exclusion criteria. There was a significant difference in the abundance of 144 GM taxa between DN patients and controls. By employing the MR technique, 13 bacteria were pinpointed as having a causal link to DN (including 3 unknown GM taxa). Even after Bonferroni correction, the protective impact of the phylum Proteobacteria and genus Dialister (Sequeira et al. Nat Microbiol. 5:304-313, 2020; Liu et al. EBioMedicine. 90:104527, 2023) and the harmful impact of the genus Akkermansia, family Verrucomicrobiaceae, order Verrucomicrobia and class Verrucomicrobiae on DN remained significant. No noticeable heterogeneity or horizontal pleiotropy was detected in the instrumental variables (IVs). However, reverse MR investigations have failed to reveal any substantial causal relationship between DN and the GM.

Differences in the GM among DN patients and healthy controls are explored in observational studies. We verified the possible connection between certain genetically modified genera and DN, thereby emphasizing the connection between the "gut-kidney" axis and new insights into the GM's role in DN pathogenesis underlying DN. Investigations into this association are necessary, and novel biomarkers for the development of targeted preventive strategies against DN are needed.

Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are increasingly linked to mitochondrial dysfunction and neuroinflammation. Central to this link are mitochondrial damage-associated molecular patterns (mtDAMPs), including mitochondrial DNA, ATP, and reactive oxygen species, released during mitochondrial stress or damage. These mtDAMPs activate inflammatory pathways, such as the NLRP3 inflammasome and cGAS-STING, contributing to the progression of neurodegenerative diseases. This review delves into the mechanisms by which mtDAMPs drive neuroinflammation and discusses potential therapeutic strategies targeting these pathways to mitigate neurodegeneration. Additionally, it explores the cross-talk between mitochondria and the immune system, highlighting the complex interplay that exacerbates neuronal damage. Understanding the role of mtDAMPs could pave the way for novel treatments aimed at modulating neuroinflammation and slowing disease progression, ultimately improving patient outcome.

Neutrophils release neutrophil extracellular traps (NETs) as part of a healthy host immune response. NETs physically trap and kill pathogens as well as activating and facilitating crosstalk between immune cells and complement. Excessive or inadequately resolved NETs are implicated in the underlying pathophysiology of sepsis and other inflammatory diseases, including amplification of the inflammatory response and inducing thrombotic complications. Here, we review the growing evidence implicating neutrophils and NETs as central players in the dysregulated host immune response. We discuss potential strategies for modifying NETs to improve patient outcomes and the need for careful patient selection.

Oxidative stress (OS) and inflammation play essential roles in the development of diabetic nephropathy (DN). Tirzepatide (TZP) has a protective effect in diabetes. However, its underlying mechanism in DN remains unclear. DN model mice were induced by intraperitoneal injection of streptozotocin (STZ; 60 mg/kg), followed by administration of different doses of TZP (3 and 10 nmol/kg) via intraperitoneal injection for 8 weeks. The effects of TZP on DN were evaluated by detecting DN-related biochemical indicators, kidney histopathology, apoptosis, OS, and inflammation levels. Additionally, to further reveal the potential mechanism, we investigated the role of TZP in modulating the IL-17 pathway. TZP reduced serum creatinine (sCR), blood urea nitrogen (BUN), and advanced glycosylation end products (AGEs) levels, while simultaneously promoting insulin secretion in diabetic mice. Additionally, TZP attenuated tubular and glomerular injury and reduced renal apoptosis levels. Further studies found that TZP increased the levels of SOD and CAT, and decreased MDA. Meanwhile, TZP also reduced the expression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in both mouse serum and kidney homogenates. TZP effectively inhibited the IL-17 pathway, and subsequent intervention with an IL-17 pathway agonist (IL-17A) reversed the suppressive effects of TZP on OS and inflammation. TZP can improve DN by inhibiting OS and inflammation through the suppression of the IL-17 pathway.

Chronic fatigue syndrome (CFS), as a complex, multisystemic, and multisystemic disorder affecting multiple organs and systems, often accompanies by symptoms such as post-exercise discomfort, sleep disorders, cognitive difficulties, and orthostatic intolerance. Jingfang Granule (JFG) is a traditional Chinese medicine that have significant protective effects on CFS, but the mechanism is still vague.

This study was designed to evaluate the protective mechanism of JFG on mice with CFS.

The combined stimuli method was used to establish the mice CFS model, and JFG was orally administered. The body weight, exhaustion swimming training and tail suspension test were assayed every 7 days to evaluate the improvement of JFG on CFS. Lactic acid, adenosine triphosphate (ATP), malondialdehyde (MDA), superoxide dismutase (SOD), reactive oxygen species (ROS), IL-1β, TNF-α, IL-6 in serum and liver glycogen, muscle glycogen in muscle were analyzed. Transmission electron microscopy was used to detect mitochondrial morphology. The regulatory networks were investigated by proteomics and central carbon metabolomics, which were verified by Western blot.

JFG reversed the loss of weight and reduce of exhaust swimming time (P < 0.05) induced by CFS in mice, and increased the tail suspension time (P < 0.05), indicating that JFG has an improving effect on CFS. Meanwhile, JFG increased the spleen index (P < 0.05), decreased the thymus index (P < 0.05) and cardiac index (P < 0.05), inhibited the secretion of Lactic acid (P < 0.05), and increased the content of liver glycogen (P < 0.05), muscle glycogen (P < 0.05), and ATP (P < 0.05), and improved mitochondrial morphology in mice with CFS. JFG also inhibited the release of TNF-α (P < 0.05), IL-1β (P < 0.05) and IL-6 (P < 0.05) in serum by inhibiting TLR4/NF-κB signaling pathway and NLRP3 inflammasome signaling pathway, and inhibited oxidative stress by activating Nrf2/HO-1/NQO1 axis. Integrated central carbon metabolomics, proteomics and Western blot showed that JFG intervened in CFS by increasing the expression of Idh1 (P < 0.05) and Idh2 (P < 0.01) to promote tricarboxylic acid (TCA) cycle.

This study confirmed that JFG promoted the TCA cycle by increasing the expression of Idh1 and Idh2, and then inhibited inflammation and oxidative stress to prevent CFS injury, which provided a potential drug candidate for CFS treatment.

Diabetic nephropathy (DN) is a common diabetes-related complication with unclear underlying pathological mechanisms. Although recent studies have linked glycolysis to various pathological states, its role in DN remains largely underexplored.

In this study, the expression patterns of glycolysis-related genes (GRGs) were first analyzed using the GSE30122, GSE30528, and GSE96804  datasets, followed by an evaluation of the immune landscape in DN. An unsupervised consensus clustering of DN samples from the same dataset was conducted based on differentially expressed GRGs. The hub genes associated with DN and glycolysis-related clusters were identified via weighted gene co-expression network analysis (WGCNA) and machine learning algorithms. Finally, the expression patterns of these hub genes were validated using single-cell sequencing data and quantitative real-time polymerase chain reaction (qRT-PCR).

Eleven GRGs showed abnormal expression in DN samples, leading to the identification of two distinct glycolysis clusters, each with its own immune profile and functional pathways. The analysis of the GSE142153 dataset showed that these clusters had specific immune characteristics. Furthermore, the Extreme Gradient Boosting (XGB) model was the most effective in diagnosing DN. The five most significant variables, including GATM, PCBD1, F11, HRSP12, and G6PC, were identified as hub genes for further investigation. Single-cell sequencing data showed that the hub genes were predominantly expressed in proximal tubular epithelial cells. In vitro experiments confirmed the expression pattern in NC.

Our study provides valuable insights into the molecular mechanisms underlying DN, highlighting the involvement of GRGs and immune cell infiltration.

Type 2 diabetes (T2D) has been linked to changes in DNA methylation levels, which can, in turn, alter transcriptional activity. However, most studies for epigenome-wide associations between T2D and DNA methylation comes from cross-sectional design. Few large-scale investigations have explored these associations longitudinally over multiple time-points.

In this longitudinal study, we examined data from the Cooperative Health Research in the Region of Augsburg (KORA) F4 and FF4 studies, conducted approximately seven years apart. Leucocyte DNA methylation was assessed using the Illumina EPIC and 450K arrays. Linear mixed-effects models were employed to identify significant associations between methylation sites and diabetes status, as well as with fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), homoeostasis model assessment of beta cell function (HOMA-B), and homoeostasis model assessment of insulin resistance (HOMA-IR). Interaction effects between diabetes status and follow-up time were also examined. Additionally, we explored CpG sites associated with persistent prediabetes or T2D, as well as the progression from normal glucose tolerance (NGT) to prediabetes or T2D. Finally, we assessed the associations between the identified CpG sites and their corresponding gene expression levels.

A total of 3,501 observations from 2,556 participants, with methylation measured at least once across two visits, were included in the analyses. We identified 64 sites associated with T2D including 15 novel sites as well as known associations like those with the thioredoxin-interacting protein (TXNIP) and ATP-binding cassette sub-family G member 1 (ABCG1) genes. Of these, eight CpG sites exhibited different rates of annual methylation change between the NGT and T2D groups, and seven CpG sites were linked to the progression from NGT to prediabetes or T2D, including those annotated to mannosidase alpha class 2a member 2 (MAN2A2) and carnitine palmitoyl transferase 1 A (CPT1A). Longitudinal analysis revealed significant associations between methylation and FPG at 128 sites, HbA1c at 41 sites, and HOMA-IR at 57 sites. Additionally, we identified 104 CpG-transcript pairs in whole blood, comprising 40 unique CpG sites and 96 unique gene transcripts.

Our study identified novel differentially methylated loci linked to T2D as well as to changes in diabetes status through a longitudinal approach. We report CpG sites with different rates of annual methylation change and demonstrate that DNA methylation associated with T2D is linked to following transcriptional differences. These findings provide new insights into the molecular mechanisms of diabetes development.

The disrupted homeostasis of branched-chain amino acids (BCAAs, including leucine, isoleucine, and valine) has been strongly correlated with diabetes with a potential causal role. However, the relationship between BCAAs and diabetic kidney disease (DKD) remains to be established. Here, we show that the elevated BCAAs from BCAAs homeostatic disruption promote DKD progression unexpectedly as an independent risk factor.

Similar to other tissues, the suppressed BCAAs catabolic gene expression and elevated BCAAs abundance were detected in the kidneys of type 2 diabetic mice and individuals with DKD. Genetic and nutritional studies demonstrated that the elevated BCAAs from systemic disruption of BCAAs homeostasis promoted the progression of DKD. Of note, the elevated BCAAs promoted DKD progression without exacerbating diabetes in the animal models of type 2 DKD. Mechanistic studies demonstrated that the elevated BCAAs promoted fibrosis-associated epithelial-mesenchymal transition (EMT) by enhancing the activation of proinflammatory macrophages through mTOR signaling. Furthermore, pharmacological enhancement of systemic BCAAs catabolism using small molecule inhibitor attenuated type 2 DKD. Finally, the elevated BCAAs also promoted DKD progression in type 1 diabetic mice without exacerbating diabetes.

BCAA homeostatic disruption serves as an independent risk factor for DKD and restoring BCAA homeostasis pharmacologically or dietarily represents a promising therapeutic strategy to ameliorate the progression of DKD.

Recent technological advancements and environmental changes are leading to an increase in various diseases such as obesity, fibrosis, metabolic disorders, and degenerative diseases associated with aging. Additionally, micro- and nanoplastics are emerging as as potential contributors to many of these conditions, posing a serious threat to human health. This special issue aims to explore new directions and opportunities for future drug development through recent review articles published in the issue, focusing on these key medical topics.

Phillygenin (PHI), a main bioactive compound found in the fruit of Forsythia suspensa, exhibits antiviral, antioxidant, anti-inflammatory, and antihypertensive activities. However, the molecular mechanisms underlying its effects on diabetic nephropathy (DN) remain unclear.

To evaluate the therapeutic effects of PHI on DN and elucidate the molecular mechanisms involved.

Cell viability assays and RNA-seq analyses were performed to identify potential mechanisms through which PHI regulates HG-induced MPCs. The therapeutic efficacy of PHI was assessed in both DN cells and mouse models. Cytokine levels were measured using ELISA, while the expression levels of key signaling pathways, including TLR4/MyD88/NF-κB and PI3K/AKT/GSK3β along with downstream effectors were analyzed via immunoblotting, immunofluorescence, and immunohistochemical staining.

PHI inhibited inflammatory responses and alleviated apoptosis by reducing the expression levels of IL-6, TNF-α, IL-1β, TLR4, MyD88, NF-κB, and cleaved caspase-3, while enhancing the phosphorylation of PI3K, AKT, GSK3β (Ser9), and pro-caspase-3 in MPCs under HG conditions in vitro. Additionally, in vivo experiments demonstrated that treatment with PHI (50 mg/kg) in db/db mice effectively improved renal function and attenuated kidney injury by reducing the urinary albumin-to-creatinine ratio (UACR), mitigating podocyte apoptosis, and inhibiting inflammatory via modulation of the TLR4/MyD88/NF-κB and PI3K/AKT/GSK3β signaling pathways.

PHI inhibits inflammation and apoptosis in vitro and alleviates diabetic kidney injury in db/db mice by interfering TLR4/MyD88/NF-κB and PI3K/AKT/GSK3β signaling pathways. Thus, this study reveals for the first time that PHI is a potential novel therapeutic agent for DN.

NLRP3 inflammasome immoderate activation results in the occurrence of various inflammatory diseases, but the clinic medications targeting NLRP3 inflammasome are still not available currently. The strategy of drug repurposing can reorient the direction of therapy, which is an indispensable method of drug research. In this study, an antimicrobial agent chlorquinaldol (CQ) was conducted to assess the effect on NLRP3 inflammasome and novel clinical value on NLRP3-driven diseases.

The effect of CQ on NLRP3 inflammasome activation and pyroptosis was studied in mouse and human macrophages. ASC oligomerization, intracellular potassium, reactive oxygen species production, and NLRP3-ASC interaction were used to evaluate the suppression mechanism of CQ on inflammasome activation. Finally, the ameliorative effects of CQ in the model of LPS-induced peritonitis, dextran sodium sulfate (DSS)-induced colitis, and monosodium urate (MSU)-induced gouty arthritis were evaluated in vivo.

CQ is a highly powerful NLRP3 inhibitor that has feeble impact on the NLRC4 or AIM2 inflammasome activation in mouse and human macrophages. Further study indicated that CQ exhibits its suppression effect on NLRP3 inflammasome by blocking NLRP3-ASC interaction and hydroxyl on the benzene ring is vital for the assembly and activation of NLRP3 inflammasome. Furthermore, in vivo experiments demonstrated that administration of CQ has outstanding therapeutic action on LPS-induced peritonitis, DSS-induced colitis, and MSU-induced gouty inflammation in mice.

Collectively, the current study discoveries the antimicrobial agent CQ as a potentially specific NLRP3 inhibitor, and its use provides a feasible therapeutic approach for the treatment of NLRP3-driven diseases.

In contemporary microbial research, the exploration of interactions between microorganisms and multicellular hosts constitutes a burgeoning field. The gut microbiota is increasingly acknowledged as a pivotal contributor to various disorders within the endocrine system, encompassing conditions such as diabetes and thyroid diseases. A surge in research activities has been witnessed in recent years, elucidating the intricate interplay between the gut microbiota and disorders of the endocrine system. Simultaneously, fecal microbiota transplantation (FMT) has emerged as a focal point, garnering substantial attention in both biomedical and clinical spheres. Research endeavors have uncovered the remarkable therapeutic efficacy of FMT across diverse diseases, with particular emphasis on its application in addressing type 2 diabetes mellitus (T2DM) and associated com-plications. Consequently, this manuscript accentuates the intimate connection between the gut microbiota and disorders within the endocrine system, with a specific focus on exploring the potential of FMT as an intervention in the therapeutic landscape of T2DM and its complications. Furthermore, the article scrutinizes concerns inherent in treatment modalities centered around the gut microbiota, proposing viable solutions to address these issues.

Diabetic nephropathy (DN) is a common and severe microvascular complication of diabetes. Mitochondrial dysfunction and immune inflammation are important factors in the pathogenesis of DN. However, the specific mechanisms and their intricate interactions in DN remain unclear. Besides, there are no effective specific predictive or diagnostic biomarkers for DN so far. Therefore, this study aims to elucidate the role of mitochondrial-related genes and their possibility as predictive or diagnostic biomarkers, as well as their crosstalk with immune infiltration in the progression of DN.

Based on the GEO database and limma R package, the differentially expressed genes (DEGs) of DN were identified. Mitochondrial-related DEGs (MitoDEGs) were then obtained by intersecting these DEGs with mitochondria-related genes from the MitoCarta 3.0 database. Subsequently, the candidate hub genes were further screened by gene co-expression network analysis (WGCNA), and verified mRNA levels of these genes by real-time quantitative PCR (qRT-PCR) in high-glucose-treated human proximal tubular (HK-2) cells. The verified hub genes were utilized to construct a combined diagnostic model for DN, with its diagnostic efficacy assessed across the GSE30122 and GSE96804 datasets. Additionally, the immune infiltration pattern in DN was assessed with the CIBERSORT algorithm, and the Nephroseq v5 database was used to analyze the correlation between hub genes and clinical features of DN.

Seven mitochondria-related candidate hub genes were screened from 56 MitoDEGs. Subsequently, the expression levels of six of them, namely EFHD1, CASP3, AASS, MPC1, NT5DC2, and BCL2A1, exhibited significant inter-group differences in the HK-2 cell model. The diagnostic model based on the six genes demonstrated good diagnostic efficacy in both training and validation sets. Furthermore, correlation analysis indicated that EFHD1 and AASS, downregulated in DN, are positively correlated with eGFR and negatively with serum creatinine. Conversely, CASP3, NT5DC2, and BCL2A1, upregulated in DN, show opposite correlations. In addition, spearman analysis revealed that the six hub genes were significantly associated with the infiltration of immune cells, including M1 and M2 macrophages, mast cells, resting NK cells, gamma delta T cells, and follicular helper T cells.

This study elucidated the characteristics of mitochondria-related genes and their correlation with immune cell infiltration in DN, providing new insights for exploring the pathogenesis of DN and facilitating the identification of new potential biomarkers and therapeutic targets.

Kidney fibrosis is the common final pathway of virtually all advanced forms of chronic kidney disease (CKD) including diabetic nephropathy (DN), IgA nephropathy (IgAN) and membranous nephropathy (MN), with complex mechanism. Comparative gene expression analysis among these types of CKD may shed light on its pathogenesis. Therefore, we conducted this study aiming at exploring the common and specific fibrosis-related genes involved in different types of CKD.

Kidney biopsy specimens from patients with different types of CKD and normal control subjects were analyzed using the NanoString nCounter® Human Fibrosis V2 Panel. Genes differentially expressed in all fibrotic DN, IgAN and MN tissues compared to the normal controls were regarded as the common fibrosis-related genes in CKD, whereas genes exclusively differentially expressed in fibrotic DN, IgAN or MN samples were considered to be the specific genes related to fibrosis in DN, IgAN and MN respectively. Quantitative real-time PCR (qRT-PCR) was performed to validate the expression of the selected genes.

Protein tyrosine phosphatase receptor type C (PTPRC), intercellular cell adhesion molecule-1 (ICAM1), vascular cell adhesion molecule-1 (VCAM1), interleukin 10 receptor alpha (IL10RA) and CC chemokine receptor 2 (CCR2) were identified as the potential common genes for kidney fibrosis in different types of CKD, while peroxisome proliferator-activated receptor alpha (PPARA), lactate oxidase (LOX), secreted phosphoprotein 1 (SPP1) were identified as the specific fibrosis-associated genes for DN, IgAN and MN respectively. qRT-PCR demonstrated that the expression levels of these selected genes were consistent with the NanoString analysis.

There were both commonalities and differences in the mechanisms of fibrosis in different types of CKD, the commonalities might be used as the common therapeutic targets for kidney fibrosis in CKD, while the differences might be used as the diagnostic markers for DN, IgAN and MN respectively. Inflammation was highly relevant to the pathogenesis of fibrosis. This study provides further insight into the pathophysiology and treatment of fibrotic kidney disease.

More evidence have shown that the combination of immune and inflammatory mechanism was critical in diabetic nephropathy (DN). However, the relationship between CD4+ T cells and the development of DN is still unclear. Therefore, this study will focus on this issue from the perspective of clinicopathology.

From September 2019 to December 2022, a total of 112 adult patients with DN were enrolled in the study. According to the density of CD4+ T cell infiltration based on immunostaining, the patients were divided into high-CD4 group (56 patients) and low-CD4 group (56 patients). Another 25 diabetic patients with minimal change disease (non-diabetic nephropathy, NDN) was reviewed as control group in clinical and molecular analysis. The clinical parameters, morphological features, and molecular characteristics were compared. The predictive value of CD4+ T cells for DN prognosis was also investigated.

DN patients in the high-CD4 group suffered from higher proteinuria and lower estimated glomerular filtration rate (eGFR) level than those in the low-CD4 group and NDN patients. Renal biopsy in the high-CD4 group presented with more severe glomerular lesions, higher density of interstitial inflammation, and more severe tubular atrophy/interstitial fibrosis than in the low-CD4 group. Multivariate logistic analysis indicated that the density of CD4+ T cell infiltration could independently predict the severity of tubular atrophy/interstitial fibrosis. In addition, more severe mitochondrial damage of renal tubular epithelial cells and a more obvious expression of Bcl6, IL-6, STAT3, and TGFβ1 were observed in DN patients of the high-CD4 group, indicating the possible mechanism of CD4+ T cells involving the progression of DN. Multivariate Cox regression analysis revealed that a higher intensity of interstitial CD4+ T cell deposition remained as an independent predictor of the double endpoint with doubling of baseline serum creatinine or end-stage renal disease.

The high density of CD4+ T cell infiltration was associated with renal function decline and severity of renal lesions and predicted poor renal survival for DN patients.

Diabetic kidney disease (DKD) is a significant complication of diabetes and a major cause of end-stage renal disease. Affecting around 40% of diabetic patients, DKD poses substantial economic burdens due to its prevalence worldwide. The primary clinical features of DKD include the leakage of proteins into the urine, altered glomerular filtration, and an increased risk of cardiovascular diseases. Current treatments focus on managing hypertension and hyperglycemia to slow the progression of DKD. These include the use of SGLT2 inhibitors to control blood sugar and ACE inhibitors to reduce blood pressure. Despite these measures, current treatments do not cure DKD and fail to address its underlying causes. Emerging research highlights mitochondrial dysfunction as a pivotal factor in DKD progression. The kidneys' high energy requirements make them particularly susceptible to disturbances in mitochondrial function. In DKD, mitochondrial damage leads to reduced energy production and increased oxidative stress, exacerbating tissue damage. Mitochondrial DNA (mtDNA) damage is a key aspect of this dysfunction, with studies suggesting that changes in mtDNA copy number can serve as biomarkers for the progression of the disease. Efforts to target mitochondrial dysfunction are gaining traction as a potential therapeutic strategy. This includes promoting mitochondrial health through pharmacological and lifestyle interventions aimed at enhancing mitochondrial function and reducing oxidative stress. Such approaches could lead to more effective treatments that directly address the DKD.

Diabetic nephropathy (DN) is a common microvascular complication of diabetes mellitus and the main cause of chronic renal failure. This study explored the potential immunomodulation-related genes (IRGs) in DN using bioinformatics.

IRGs were identified using GeneCards, and differentially expressed genes were identified using the GSE99339, GSE96804, and GSE30122 datasets. We conducted enrichment analyses using Gene Ontology, gene set enrichment analysis (GSEA), and Kyoto Encyclopedia of Genes and Genomes to identify the associated signaling pathways. Prognostic models were constructed using Least Absolute Shrinkage and Selection Operator regression. The predictive power of IRGs was evaluated using receiver operating characteristic (ROC) curves. Furthermore, we utilized ssGSEA to determine the relative abundance of immune cell infiltration. The expression of five significant IRGs was further validated using immunohistochemistry (IHC) in individuals with DN and real-time PCR (RT-PCR) in animal experiments.

In total, 17 immunomodulation-related differentially expressed genes were identified, which were enriched in immune-associated pathways and inflammation. GSEA unveiled substantial enrichments in metabolic irregularities and the structural composition of the extracellular matrix. ROC analysis results revealed that the diagnostic efficacy of IFNAR2 and CASP3 was comparatively high. Notably, we identified potential IRGs for DN, including CASP3, LGALS9, and SST, using IHC and RT-PCR.

CASP3, LGALS9, and SST are potential IRGs in patients with DN. Our findings may offer a theoretical basis for developing more focused and innovative immunotherapy approaches for patients with DN.

Renal interstitial fibrosis (RIF) is a significant pathological change in diabetic kidney disease (DKD) that can be induced by endothelial-to-mesenchymal transition (EndMT). Lymphangiogenesis, mediated by the vascular endothelial growth factor-C (VEGF-C)/vascular endothelial growth factor receptor-3 (VEGFR-3) pathway, plays a crucial role in the development of RIF in DKD. Although numerous studies have demonstrated the efficacy of empagliflozin in treating renal injury, its effects on lymphangiogenesis in DKD-related RIF and the underlying mechanisms remain unclear. In the present study, significant lymphangiogenesis was assessed in the renal interstitium of patients with DKD. We subsequently explored the relationship between DKD-related RIF and lymphangiogenesis in mouse models, high-glucose (HG)-stimulated renal HK-2 cell lines, and human lymphatic endothelial cells (hLECs). Additionally, we evaluated the effects of empagliflozin on these processes. The results revealed that HG induces lymphangiogenesis, which exacerbates RIF by promoting inflammatory responses. Furthermore, hLECs directly contributed to the progression of DKD-related RIF through EndMT. Further analysis revealed that tubular epithelial cells (TECs) act as effector cells for VEGF-C, with the epithelial-to-mesenchymal transition (EMT) of TECs occurring concurrently with the EndMT of lymphatic vessels. Empagliflozin inhibited RIF in DKD by suppressing the VEGF-C/VEGFR3 pathway and reducing lymphangiogenesis. In conclusion, this study elucidates the interplay between lymphangiogenesis, EndMT, and RIF in DKD and provides new insights into the mechanism by which empagliflozin treats DKD.

Accumulation of extracellular matrix (ECM) proteins in the glomerular mesangial region is a typical hallmark of diabetic nephropathy (DN). However, the molecular mechanism underlying ECM accumulation in the mesangium of DN patients remains unclear. The present study aims to establish a connection between extracellular proteins and DN with the goal of identifying potential biomarkers for this condition.

Differentially expressed genes (DEGs) between DN kidney tissue and healthy kidney tissue were analyzed using the public data GSE166239. Two gene lists encoding extracellular proteins were then utilized to identify extracellular protein-differentially expressed genes (EP-DEGs). Functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, were performed on these EP-DEGs. A protein-protein interaction (PPI) network was established to identify key EP-DEGs. Furthermore, the diagnostic ability, immune cell infiltration, and clinical relevance of these EP-DEGs were investigated. Immunohistochemistry (IHC) staining of paraffin-embedded renal tissues was performed to validate the accuracy of the bioinformatic results.

A total of 1204 DEGs were identified, from which 162 EP-DEGs were further characterized by overlapping with extracellular protein gene lists. From the PPI network analysis, five EP-DEGs (e.g., TNF, COL1A1, FN1, MMP9, and TGFB1) were identified as candidate biomarkers. TNF, COL1A1, and MMP9 had a high diagnostic accuracy for DN. Assessment of immune cell infiltration revealed that the expression of TNF was positively associated with resting dendritic cells (DCs) (r = 0.85, P < 0.001) and M1 macrophages (r = 0.62, P < 0.05), whereas negatively associated with regulatory T cells (r = - 0.62, P < 0.05). Nephroseq v5 analysis demonstrated a negative correlation between the estimated glomerular filtration rate (eGFR) and TNF expression (r = - 0.730, P = 0.025). Gene set enrichment analysis (GSEA) revealed significant enrichment of glycosaminoglycan (GAG) degradation in the high-TNF subgroup. IHC staining of renal tissues confirmed significantly elevated TNF-a expression and decreased hyaluronic acid (HA) levels in the DN group compared to controls (both P < 0.05), with a negative correlation observed between TNF-a and HA (r = - 0.691, P = 0.026).

Our findings suggest that TNF may play a pivotal role in the progress of DN by driving ECM accumulation, and this process might involve GAG degradation pathway activation.

Diabetic nephropathy (DN) is a globally widespread complication of diabetes mellitus (DM). Research indicates that pioglitazone and linagliptin mitigate the risk of DN by reducing inflammation, oxidative stress, and fibrosis. The role of tamsulosin in DN is less studied, but it may contribute to reducing oxidative stress and inflammatory responses. The protective effects of combining pioglitazone, linagliptin, and tamsulosin on the kidneys have scarcely been investigated. This study examines the individual and combined effects of these drugs on DN in Wistar rats. Diabetic rats were treated with tamsulosin, pioglitazone, and linagliptin for six weeks. We assessed food and water intake, estimated glomerular filtration rate (eGFR), histological markers, urea, creatinine, glucose, NF-κB, IL-1, IL-10, TGF-β, and Col-IV using immunofluorescence and qPCR. The DN group exhibited hyperglycaemia, reduced eGFR, and tissue damage. Tamsulosin and linagliptin improved eGFR, decreased urinary glucose, and repaired tissue damage. Pioglitazone and its combinations restored serum and urinary markers and reduced tissue damage. Linagliptin lowered serum creatinine and tissue injury. In conclusion, tamsulosin, linagliptin, and pioglitazone demonstrated renoprotective effects in DN.

The objective of our research was to investigate the specific mechanism of FTO in diabetic kidney disease (DKD) progression.

The DKD model was established with renal tubular epithelial HK-2 cells and mice in vitro and in vivo. The N6-methyladenosine (m6A) content in cells was detected using dot plot assay and the m6A levels of NLRP3 was detected with the MeRIP assay. The mRNA and protein levels were tested with real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) and western blot. The IL-1β and IL-18 levels were assessed with enzyme-linked immunosorbent assay (ELISA). The cell viability was measured by cell counting kit (CCK)-8 assay and cell pyroptosis was determined with Annexin V and propidium iodide (PI) double staining followed by flow cytometry analysis. RNA-binding protein immunoprecipitation (RIP) and dual luciferase reporter assays were conducted to detect the interaction between FTO and NLRP3. m6A levels were detected by Me-RIP assay. The renal injury was measured by observing the renal morphology and urine and blood levels of relevant indicators.

The results indicated that high glucose treatment induced HK-2 cell pyroptosis. m6A levels were prominently elevated in high glucose treated HK-2 cells while FTO expression were significantly down-regulated. FTO over-expression promoted cell viability but inhibited pyroptosis of HK-2 cells under high glucose (HG) treatment. Moreover, FTO could inhibit NLRP3 expression. RIP and Me-RIP assays indicated that FTO could bind with NLRP3 and regulate its m6A modification level. Further luciferase assay confirmed that FTO binds with the 233-237 bp region of NLRP3. NLRP3 neutralized the function of FTO in the HG stimulated HK-2 cells. In vivo, the H&E staining showed that FTO over-expression alleviated the kidney injury and suppressed the pyroptosis induced by DKD.

We found that FTO could inhibit the DKD progression in vivo and in vitro by regulated the m6A modification of NLRP3.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, with an increasing prevalence worldwide, but its pathomechanisms remain incompletely understood. Accumulating evidence suggests that immunity plays an important role in the development of DN. Many papers have been published in the field over the last 20 years, but there has been no bibliometric review of the research hotspots and trends in the field. This study aimed to assess the current research status and future trends of the link between immune and DN using bibliometric analysis.

Publications on the association between immunity and DN from 2004 to 2023 were retrieved from the Web of Science Core Collection database and screened according to inclusion criteria. VOSviewer and CiteSpace software were employed to visualize research trends and hotspots in the field. Data including author, institution, country, journal, reference, and keyword were analyzed.

Ultimately 1246 publications meeting the criteria were included in the bibliometric analysis, involving 838 articles (84.96%) and 408 reviews (15.04%). The literature covered 81 countries and regions, 1751 institutions, and 6584 authors. The top 2 countries in terms of the number of publications were China (435) and the United States (318), and they collaborated most frequently. The United States had the highest number of citations for published papers (18,161), far exceeding the other countries. England had 38 publications but had the highest average number of citations (92.32). The University of California system was the most prolific institution (25 papers, 1062 citations, 42.48 citations per paper). Frontiers in Immunology was the most prolific journal in the field (30 papers). The most cited journal was Kidney International (863 citations). The analysis of keywords and references showed that inflammation, ferroptosis, and lipid metabolism may be future research hotspots in this field.

The number of publications related to immunity and DN has increased annually over the past 20 years, with a significant increase in the last 3 years especially. Our results identified research hotspots and trends in the field. These findings provide valuable perspectives for future research, enhancing our understanding of the immune-related mechanisms of DN and exploring potential therapeutic strategies.

Oridonin possesses remarkable anti-inflammatory, immunoregulatory properties. However, the renoprotective effects of oridonin and the underlying molecular mechanisms in diabetic nephropathy (DN). We hypothesized that oridonin could ameliorate diabetes‑induced renal fibrosis.

Streptozocin (STZ)-induced diabetic rats were provided with a high-fat diet to establish a type 2 diabetes mellitus (T2DM) animal model, and then treated with Oridonin (10, 20 mg/kg/day) for two weeks. Kidney function and renal fibrosis were assessed. High glucose-induced human renal proximal tubule epithelial cells (HK-2) were also treated with oridonin. The expression of inflammatory factors and fibrotic markers were analyzed.

Oridonin treatment preserved kidney function and markedly limited the renal fibrosis size in diabetic rats. The renal fibrotic markers were inhibited in the oridonin 10 mg/kg/day and 20 mg/kg/day groups compared to the T2DM group. The expression of thioredoxin-interacting proteins/ nod-like receptor protein-3 (TXNIP/NLRP3) and nuclear factor (NF)‑κB pathway decreased, while that of peroxisome proliferator-activated receptor-gamma (PPARγ) increased in the oridonin treatment group compared to the non-treated group. In vitro, PPARγ intervention could significantly regulate the effect of oridonin on the high glucose-induced inflammatory changes in HK-2 cells.

Oridonin reduces renal fibrosis and preserves kidney function via the inhibition of TXNIP/NLRP3 and NF‑κB pathways by activating PPARγ in rat T2DM model, which indicates potential effect of oridonin in the treatment of DN.

The high prevalence of diabetes mellitus (DM) poses a significant public health challenge, with diabetic kidney disease (DKD) as one of its most serious consequences. It has become increasingly clear that type 2 DM (T2D) and the complications of DKD are not purely metabolic disorders. This review outlines emerging evidence related to the step-by-step contribution of macrophages to the development and progression of DKD in individuals who specifically develop T2D as a result of obesity. The macrophage is a prominent inflammatory cell that contributes to obesity, where adipocyte hypertrophy leads to macrophage recruitment and eventually to the expansion of adipose tissue. The recruited macrophages secrete proinflammatory cytokines, which cause systemic inflammation, glucose dysregulation, and insulin sensitivity, ultimately contributing to the development of T2D. Under such pathological changes, the kidney is susceptible to elevated glucose and thereby activates signaling pathways that ultimately drive monocyte recruitment. In particular, the early recruitment of proinflammatory macrophages in the diabetic kidney produces inflammatory cytokines/chemokines that contribute to inflammation and tissue damage associated with DKD pathology. Macrophage activation and recruitment are crucial inciting factors that also persist as DKD progresses. Thus, targeting macrophage activation and function could be a promising therapeutic approach, potentially offering significant benefits for managing DKD at all stages of progression.

This study aimed to elucidate the nature and extent of the associations between diabetes mellitus (DM) and migraine through a systematic review and meta-analysis.

We searched the PubMed, Web of Science, and Scopus databases without a specified start date until June 2, 2024. Cross-sectional and cohort studies analyzing the risk of migraine in individuals with DM and vice versa were included. Studies without at least age and sex adjustments were excluded. Data were extracted to calculate odds ratios (ORs) and hazard ratios (HRs). Risk of bias was assessed using the Newcastle-Ottawa Quality Assessment Scale.

Eight cross-sectional studies (131,361 patients with DM and 1,005,604 patients with migraine) and four cohort studies (103,205 patients with DM patients and 32,197 patients with migraine) were included. Meta-analyses of the cross-sectional studies showed no significant overall association between DM and migraine. Subgroup analyses revealed that type 1 diabetes reduced the odds of having migraine (OR 0.48, 95% confidence interval [CI] 0.30-0.77), while migraine without aura (MO) increased the odds of having DM (OR 1.19, 95% CI 1.02-1.39). The cohort studies indicated that DM decreased the risk of developing migraine (HR 0.83, 95% CI 0.76-0.90), and a history of migraine increased the risk of developing DM (HR 1.09, 95% CI 1.01-1.17).

DM, particularly type 1 diabetes, is negatively associated with migraine occurrence, whereas migraine, especially MO, is positively associated with DM occurrence. However, most of the results remained at a low or very low level of evidence, indicating the need for further research.

The role of immune cells in the pathogenesis and advancement of diabetic nephropathy (DN) is crucial. The objective of this study was to identify immune-cell-related biomarkers that could potentially aid in the diagnosis and management of DN.

The GSE96804 dataset was obtained from the Gene Expression Omnibus (GEO) database. Then, screen for intersections between differentially expressed genes (DEGs) and immune-related genes (IRGs). Identify core genes through protein-protein interaction (PPI) networks and the Cytoscape plugin. Subsequently, functional enrichment analysis was conducted. In addition, ROC analysis is performed to accurately identify diagnostic biomarkers. Apply the CIBERSORT algorithm to evaluate the proportion of immune cell infiltration. Finally, the mRNA, protein, and immunofluorescence expression of the biomarker was validated in the DN rat model.

The study yielded 74 shared genes associated with DN. Enrichment analysis indicated significant enrichment of these genes in focal adhesion, the humoral immune response, activation of the immune response, Cytokine-cytokine receptor interaction, and IL-17 signaling pathway. The optimal candidate gene VCAM1 was identified. The presence of VCAM1 in DN was further validated using the ROC curve. Analysis of immune cell infiltration matrices revealed a high abundance of monocytes, naïve B cells, memory B cells, and Macrophages M1/M2 in DN tissues. Correlation analysis identified one hub biomarker associated with immune-infiltrated cells in DN. Furthermore, our findings were validated through in vivo RT qPCR, WB, and IF techniques.

Our research indicates that VCAM1 is a signature gene associated with DN and is linked to the progression, treatment, and prognosis of DN. A comprehensive examination of immune infiltration signature genes may offer new perspectives on the clinical diagnosis and management of DN.

Renal injury, a prevalent clinical outcome with multifactorial etiology, imposes a substantial burden on society. Currently, there remains a lack of effective management and treatments. Extensive research has emphasized the diverse biological effects of natural polysaccharides, which exhibit promising potential for mitigating renal damage. This review commences with the pathogenesis of four common renal diseases and the shared mechanisms underlying renal injury. The renoprotective roles of polysaccharides in vivo and in vitro are summarized in the following five aspects: anti-oxidative stress effects, anti-apoptotic effects, anti-inflammatory effects, anti-fibrotic effects, and gut modulatory effects. Furthermore, we explore the structure-activity relationship and bioavailability of polysaccharides in relation to renal injury, as well as investigate their utility as biomaterials for alleviating renal injury. The clinical experiments of polysaccharides applied to patients with chronic kidney disease are also reviewed. Broadly, this review provides a comprehensive perspective on the research direction of natural polysaccharides in the context of renal injury, with the primary aim to serve as a reference for the clinical development of polysaccharides as pharmaceuticals and prebiotics for the treatment of kidney diseases.

Previous studies provided clues that environmental factors were closely related to diabetes incidence. However, the evidence from high-quality and large cohort studies about the effects of PM2.5, solid fuel use and greenness on the development of diabetes among middle-aged and older adults in China was scarce.

To separately investigate the independent effects of PM2.5, solid fuel use and greenness on the development of diabetes among middle-aged and older adults.

A total of 9242 participants were involved in this study extracted from the China Health and Retirement Longitudinal Study. Time-varying Cox regression was applied to detect the association of diabetes with PM2.5, solid fuel use and greenness, separately. The potential interactive effect of air pollution and greenness were explored using the relative excess risk due to interaction (RERI).

Per 10 μg/m3 increases in PM2.5 were associated with 6.0% (95% CI: 1.9, 10.2) increasing risks of diabetes incidence. Females seemed to be more susceptible to PM2.5. However, the effects of solid fuel use only existed in older and lower BMI populations, with hazard ratios (HRs) of 1.404 (1.116, 1.766) and 1.346 (1.057, 1.715), respectively. In addition, exposure to high-level greenness might reduce the risks of developing diabetes [HR = 0.801 (0.687, 0.934)]. Weak evidence of the interaction effect of PM2.5/solid fuel use and greenness on diabetes was found.

Both PM2.5 and solid fuel use were associated with the increasing incidence of diabetes. In addition, high-level greenness might be a beneficial environmental factor for reducing the risks of developing diabetes. All in all, our findings might provide valuable references for public health apartments to formulate very fruitful policies to reduce the burden of diabetes.

Both PM2.5 and solid fuel use were associated with the increasing incidence of diabetes while high-level greenness was not, which might provide valuable references for public health apartments to make policies.