Search Results (163)

Clonal hematopoiesis of indeterminate potential (CHIP) and the gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) are both linked to NLRP3-mediated cardiovascular inflammation, but their interaction has not previously been explored. This work proposes the CHIDT axis (clonal hematopoiesis–dysbiosis–TMAO), a feed-forward mechanism in which TET2 loss-of-function CHIP- and TMAO-generating Gram-negative gut dysbiosis mutually enhance cardiovascular risk. The model proceeds in three nodes. CHIP-associated intestinal immune dysregulation promotes luminal expansion of Gammaproteobacteria, which produce both trimethylamine via CntA/CntB-mediated L-carnitine oxidation and ADP-heptose as an obligate LPS biosynthetic intermediate. TMAO amplifies NLRP3 inflammasome activation through the SIRT3 → SOD2 → mtROS pathway. The evidence base of the CHIDT model is strongest for TET2-CHIP; the proposed extension to DNMT3A-CHIP rests on indirect, associative data and requires dedicated experimental confirmation before it can be considered established. TXNIP cascade, with predicted disproportionate potency in macrophages epigenetically primed by TET2 haploinsufficiency. High concentrations of TMAO have also been shown to suppress TET2 expression in endothelial cells through CYTB promoter hypermethylation, inducing NLRP3–GSDMD-dependent pyroptosis, although it remains unclear whether physiological TMAO levels can trigger this effect. Concurrently, ADP-heptose activates the ALPK1–TIFA–NF-κB pathway in bone marrow progenitors, favoring the expansion of mutant hematopoietic stem and progenitor cells. The model identifies three potential therapeutic strategies: NLRP3 inhibition, microbial TMA lyase inhibition, and microbiome-targeted reduction in Gram-negative bacteria. None has been tested in CHIP carriers stratified by plasma TMAO. Further studies in preclinical models and human cohorts integrating CHIP genotyping and TMAO quantification are needed to validate the CHIDT axis as a target for precision cardiovascular prevention. Full article

Background: Pathological aggregation of islet amyloid polypeptide (IAPP) contributes to β-cell dysfunction in type 2 diabetes. Our previous studies demonstrated that caveolin-1 (Cav-1) deficiency protects β-cells from palmitate-induced apoptosis. Microarray profiling further indicated that Cav-1 silencing alters IAPP expression. This study aimed to investigate the effects of Cav-1 depletion on IAPP secretion and expression and to explore the potential involvement of thioredoxin-interacting protein (TXNIP). Methods: We performed lentiviral-mediated Cav-1 knockdown in NIT-1 cells and isolated murine islets, and simultaneously generated an inducible β-cell-specific Cav-1 knockout (iβ-Cav1 KO) mouse model. IAPP secretion and expression were assessed by ELISA, Western blot, qPCR and immunofluorescence. The expression of IAPP-processing enzymes (PAM, PC1, and PC2) and degradation factors (IDE and BACE2) was examined. Co-immunoprecipitation (Co-IP) and immunofluorescence were performed to investigate the interaction between Cav-1 and TXNIP. Results: Cav-1 depletion significantly reduced both IAPP secretion and expression in vitro and in vivo. High-fat-diet-fed iβ-Cav1 KO mice exhibited the lowest serum IAPP levels. Mechanistically, Cav-1 depletion was associated with downregulation of PAM, PC1, and PC2 and upregulation of IDE and BACE2. Additionally, Cav-1 depletion decreased TXNIP expression. Immunofluorescence revealed co-localization of Cav-1 and TXNIP, and co-immunoprecipitation further demonstrated their direct physical interaction. Conclusions: Cav-1 is essential for IAPP secretion and expression in β-cells. The direct physical interaction between Cav-1 and TXNIP suggests that TXNIP may mediate the regulatory effects of Cav-1 on IAPP processing or secretion. These findings identify the Cav-1–TXNIP axis as a potential target for mitigating IAPP-related β-cell dysfunction. Full article

Background: Macrophage pyroptosis contributes substantially to sepsis-induced lung injury, yet effective therapeutic strategies remain limited. This study aimed to determine the protective effects of meloxicam, a non-steroidal anti-inflammatory drug, and the underlying mechanisms in this context. Methods:In vivo, CLP mice were treated with meloxicam (20 mg/kg). In vitro, LPS-primed macrophages were stimulated with ATP or nigericin in the presence or absence of meloxicam. Levels of pyroptosis-associated proteins (cleaved Caspase-1, mature IL-1β, GSDMD-NT), NLRP3 inflammasome assembly, and the CBP/TXNIP/p38 signaling axis were assessed by Western blot. Mitochondrial membrane potential (ΔΨm) and intracellular ROS were measured. Overexpression of COX-2, TXNIP, and CBP was also performed. Results: Meloxicam significantly improved survival, reduced lung injury, and suppressed pyroptosis-associated proteins in CLP mice. In vitro, meloxicam dose-dependently enhanced macrophage viability and reduced LDH, IL-1β, and IL-18 release. The protective effects of meloxicam were mediated by inhibition of NLRP3 inflammasome priming and assembly, disruption of NLRP3-ASC-pro-Caspase-1 complex formation, and suppression of ASC oligomerization. Meloxicam also inhibited the CBP/TXNIP/p38 axis, an effect reversed by TXNIP or CBP overexpression. Furthermore, meloxicam restored ΔΨm and reduced ROS accumulation; these effects were abrogated by the ROS inducer imiquimod. Importantly, the anti-pyroptotic effects of meloxicam were independent of COX-2 inhibition. Conclusions: These findings expand the pharmacological profile of meloxicam and support its repurposing as a therapeutic agent for sepsis-associated lung injury. Full article

Apoptosis maintains tissue homeostasis, and its dysregulation is closely associated with breast cancer progression and therapeutic resistance. We performed an integrative analysis of apoptosis-related signaling in breast cancer tissues across five molecular subtypes and compared these patterns with systemic apoptotic responses following cryoablation of benign fibroadenomas. Gene expression profiling was conducted using mRNA microarrays and validated by qRT-PCR and ELISA. Apoptosis pathway activity was assessed with the MSigDB HALLMARK_APOPTOSIS gene set, including intrinsic and extrinsic pathway scoring and an apoptotic balance index (ABI). MicroRNA profiling combined with in silico analyses identified potential miRNA–mRNA interactions. A progressive shift toward reduced pro-apoptotic and enhanced stress-adaptive signaling was observed with increasing tumor aggressiveness, most pronounced in triple-negative and non-luminal HER2-positive cancers. This pattern included reduced intrinsic pathway activity, decreased ABI, downregulation of pro-apoptotic genes (BIK, BMF, TXNIP), and upregulation of stress-associated or cytoprotective genes (HSPB1, PPT1). Several expression patterns were accompanied by overexpression of miRNAs (miR-582-5p, miR-421, miR-106b-5p, miR-20a-5p, miR-20b-5p, miR-93-5p) predicted to target apoptosis-related genes. In contrast, fibroadenoma cryoablation was associated with transient systemic modulation of apoptosis-related genes and proteins followed by gradual normalization. These findings highlight differences between apoptosis-related dysregulation in malignant tissue and regulated systemic responses following benign tissue injury, supporting pathway-level interpretation and identifying candidate molecular networks warranting further mechanistic and translational investigation. Full article

Extensive epidemiological evidence links psychosis (PZ)—particularly schizophrenia (SCZ)—with disproportionate periodontal destruction, suggesting shared biological vulnerability. Beyond local tissue damage, periodontitis provides a clinically accessible translational paradigm for systemic redox dysregulation, where sustained inflammatory activation coincides with measurable oxidative injury and exhaustion of antioxidant (AO) defenses across cardiometabolic and neuropsychiatric domains. In this critical narrative review, we argue that the excess periodontal burden in PZ reflects a “pathological confluence” shaped by antipsychotic-associated iatrogenic factors, rapid metabolic deterioration, and chronic oxidative distress. We appraise the thioredoxin-interacting protein (TXNIP)–NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) axis as a metabolic–redox sensor linking dysglycemia to periodontal inflammasome activation and downstream cytokine signaling, and address the advanced glycation end-products (AGEs)–receptor for advanced glycation end-products (RAGE) axis as a key immunometabolic redox pathway. We further discuss mitochondrial dysfunction, impaired mitophagy, and mitochondrial deoxyribonucleic acid (mtDNA) leakage as damage-associated molecular patterns (DAMPs) that can amplify systemic “silent inflammation”. Integrating evidence on periodontal pathogen–host interactions and redox-sensitive neuroimmune pathways (including NADPH oxidase 4 (NOX4)-linked microglial activation), we propose periodontitis as a plausible upstream amplifier that may exacerbate vascular dysfunction and compromise blood–brain barrier (BBB) integrity. Finally, we outline clinically measurable biomarker readouts to operationalize redox-informed integrated care and highlight the need for pragmatic trials targeting clinically meaningful endpoints to improve somatic longevity in PZ-spectrum populations. We acknowledge that current human evidence is largely associative and that the proposed mechanistic links remain hypothesis generating. Full article

Background/Objectives: Bleomycin is an antineoplastic antibiotic used in the management of various malignancies. Nevertheless, its benefits are constrained by the development of pulmonary fibrosis. Amentoflavone, a biflavonoid, exhibits diverse pharmacological activities, including anti-inflammatory, antiviral, antioxidant, and antitumor effects, whereas alogliptin possesses antioxidant and anti-inflammatory properties. This study aimed to assess the potential protective effects of alogliptin and/or amentoflavone in a murine model of bleomycin-induced pulmonary fibrosis and to clarify the underlying mechanisms. Methods: Fifty male C57BL/6 mice were randomly divided into 5 equal groups: control, bleomycin, bleomycin + alogliptin, bleomycin + amentoflavone, and bleomycin + alogliptin + amentoflavone. The assessed endpoints included lung weight/body weight index, lung tissue fibrotic mediators, oxidative stress parameters, proinflammatory cytokines, and pyroptotic and autophagy mediators. Also, the bronchoalveolar lavage fluid (BALF) was evaluated for total and differential leukocytic counts and lactate dehydrogenase (LDH) activity. Moreover, vascular responses to potassium chloride, phenylephrine, and carbachol, together with tracheal responses to carbachol were determined. Lung tissues were further examined histopathologically and immunohistochemically. Results: Treatment with alogliptin and/or amentoflavone significantly decreased the lung weight/body weight index and BALF LDH activity, concomitant with mitigation of lung tissue oxidative stress parameters, fibrotic mediators, apoptosis, and pyroptosis with a significant augmentation of autophagy signals, alongside marked improvement in the lung architecture and vascular and airway reactivity compared with the bleomycin group. These effects were most pronounced with animals treated with the alogliptin/amentoflavone combination. Conclusions: These findings suggest that combined alogliptin and amentoflavone may constitute a promising strategy to prevent bleomycin-induced lung fibrosis. Full article

Background: The rising incidence of CINIII, particularly in younger patients, has highlighted limitations of current surgical treatments, which can affect fertility and carry recurrence risks. This underscores an urgent clinical need for non-invasive therapies. Our study addresses this by investigating the cellular and molecular changes during CINIII progression to cervical squamous cell carcinoma (CSCC). Methods: We employed single-cell sequencing to meticulously analyze cell types and molecular mechanisms within cervical epithelial cells and their microenvironment throughout the CINIII-to-CSCC transition. Results: Key findings include the identification of Sox2 and its signaling pathway as markers for specific cervical stem cells (CCSCs) during malignant transformation. In the microenvironment, upregulated VWF, MMP2, and HTRA1 were observed in vascular endothelial cells, while TXNIP+ and ARL4D+ fibroblasts underwent transformation into myofibroblasts. Immune cell proportions notably increased, particularly macrophages, T cells, B cells, NK cells, mast cells, and neutrophils, contrasting with a decrease in non-immune cells. Furthermore, interaction analysis revealed that communication between macrophages and cervical epithelial cells was the most prominent. Conclusions: This research comprehensively details the complex cellular and molecular remodeling inherent in CINIII progression. By pinpointing specific pathways and cell populations, our findings establish a crucial framework for developing innovative, non-invasive drug therapies to delay disease progression and ultimately improve long-term reproductive outcomes for patients. Full article

The abnormal activation of the Nlrp3 (Nod-like receptor pyrin 3) inflammasome, in response to oxidative stress or impaired antioxidant defense, is linked to aging-related diseases. Previously, we have shown that Peroxiredoxin (Prdx)6 deficiency triggers reactive oxygen species (ROS)-dependent activation of Kruppel-like factor (Klf)9/Nlrp3 inflammasome in aging lens epithelial cells (LECs). Herein, we test the therapeutic efficacy of Prdx6 delivery in abating the oxidative stress-induced aberrant activation of the Klf9/NF-ĸB/Nlrp3 pathway and subsequent pyroptotic cell death in LECs and Prdx6-deficient (Prdx6^−/−) LECs. Similar to aged LECs, Prdx6-depleted LECs exhibited activation of Nlrp3 inflammasome components—including ASC, Caspase-1, IL-1β, IL-18, GSDMD—and displayed heightened sensitivity to H₂O₂/UVB-induced oxidative damage. The delivery of TAT-HA-Prdx6 or the overexpression of Prdx6 in Prdx6^−/− mLECs significantly suppressed the aberrant activation of these inflammatory components and restored redox balance by eliminating ROS levels during oxidative stress. Similarly, TAT-HA-Prdx6 effectively internalized into SRA-hLECs and suppressed the H₂O₂- and/or UVB-induced upregulation of Nlrp3 and its components. Furthermore, the oxidative stress or Prdx6 deficiency led to increased Nlrp3 promoter activity and NF-ĸB activation, accompanied by decreased cytosolic IĸBα and increased phosphorylation of IĸBα; these alterations were reversed by Prdx6 overexpression. The elevated Klf9 transcription observed in aging and Prdx6^−/− mLECs or under oxidative stress was also inhibited by Prdx6 delivery. Additionally, Prdx6^−/− mLECs and aging LECs displayed increased TXNIP and reduced TRX levels, which were normalized by Prdx6 restoration. Collectively, this study provides the first evidence that the loss of Prdx6 drives aberrant activation of Klf9/NF-ĸB/Nlrp3 inflammasome axis, leading to pyroptotic cell death. Prdx6 delivery represents a promising therapeutic strategy to rescue cells from pyroptosis (oxidative stress-induced inflammatory cell death). Full article

Particulate matter (PM) is a complex mixture of airborne solid particles and liquid droplets originating from various environmental sources, and it has been implicated in the initiation, development, and progression of pulmonary inflammation and respiratory diseases. However, the underlying associated molecular mechanisms remain unclear. Adenophora divaricate Franch. & Sav. (AD) is a medicinal herb classified within the Campanulaceae family and genus Adenophora, with a broad geographic distribution across East Asia, including Korea, Asia, and Russia. In this study, we investigated the mechanisms underlying the effects of AD on PM-induced lung inflammation in both PM-stimulated RAW264.7 cells and PM-exposed mice. Considering that the reactive oxygen species (ROS)-mediated thioredoxin-interacting protein (TXNIP) and NOD-like receptor pyrin domain containing (NLRP3) inflammasome pathway plays a role in PM-induced inflammatory responses, we focused on determining whether AD exerts its anti-inflammatory effects through modulation of this signaling pathway. The anti-inflammatory properties of the methanolic extract of AD were evaluated using PM-stimulated RAW264.7 cells and PM-exposed mice. PM was administered intranasally to mice for 7 days, whereas AD or dexamethasone was orally administered for the same duration. AD treatment significantly attenuated pulmonary inflammation, as evidenced by reduced inflammatory cell counts and decreased cytokine levels in bronchoalveolar lavage fluid. In addition, AD decreased oxidative stress marker (ROS and thiobarbituric acid reactive substances) while increasing glutathione content, leading to suppression of TXNIP/NLRP3 inflammasome expression. Histopathological analysis revealed a marked alleviation of inflammatory responses in lung tissue, characterized by diminished inflammatory cell infiltration and reduced alveolar wall thickening. Collectively, these findings suggest ROS-mediated TXNIP serves as a key regulatory factor, and AD may serve as a potential therapeutic agent for pulmonary inflammation. Full article

Prostate cancer is one of the most prevalent malignancies among men and remains a major clinical challenge due to the complex tumor microenvironment. Understanding gene expression dynamics at both cellular and spatial levels is essential for improving therapeutic strategies. In this study, we performed an integrated multi-omics analysis using single-cell RNA sequencing and spatial transcriptomics. scRNA-seq data from 15 prostate samples, including 8 normal and 7 tumor tissues, were analyzed to characterize distinct cellular populations. Spatial transcriptomic profiling was conducted on three FFPE prostate tissue sections, including adjacent normal tissue, acinar cell carcinoma, and invasive adenocarcinoma, using the standard 10x Genomics Visium FFPE platform (55 µm capture spots). Single-cell analysis revealed heterogeneity among epithelial, stromal, and immune cell populations, highlighting complex signaling networks in which myeloid cells may contribute to tumor progression through immune suppression and epithelial adaptability. Spatial transcriptomic analysis further identified region-specific expression patterns and spatially restricted tumor niches, including the regional establishment of TXNIP and BIRC3 as genes associated with metabolic stress and inflammatory survival pathways. The spatial colocalization of BIRC3 with tumor vasculature in invasive carcinoma tissue suggests a novel interaction. Our discoveries using an integrated single-cell and spatial transcriptomic approach reveal a high-resolution molecular map of prostate cancer with spatial features that may provide further therapeutic investigation. Full article

The cytotoxic effect of islet amyloid polypeptide (IAPP) misfolding and aggregation has a well-recognized role in the pathogenesis of type 2 diabetes mellitus, mediated by failure of the beta cell’s protein quality control system to rescue the cell from overwhelming proteotoxic stress induced by IAPP aggregates, ultimately leading to apoptosis. A small but growing body of research also links IAPP-mediated proteotoxic stress to the pathogenesis of type 1 diabetes and to the functional decline of transplanted islets. Among the most promising therapeutic approaches under investigation are small organic molecules that may act as direct chemical chaperones to prevent IAPP aggregation, promote the activity of endogenous chaperones, or alter gene networks of the unfolded protein response (UPR) to promote pro-survival rather than pro-apoptotic pathways in response to IAPP-mediated proteotoxic stress. Compounds warranting special attention include 4-phenylbutyrate (PBA), tauroursodeoxycholic acid (TUDCA), and epigallocatechin gallate (EGCG), as each has a growing body of evidence supporting their ability to ameliorate this process, and given that each of these are already known to have good safety profiles in humans, potentially accelerating the timeline to interventional studies. This review explores the evidence for IAPP-mediated proteotoxicity in multiple forms of diabetes, the mechanisms of cytotoxicity at different levels of the cell’s protein quality control systems, how these small organic compounds may act on these processes including new insights on the role of thioredoxin-interacting protein (TXNIP), and the current evidence supporting each of these compounds in mitigating diabetogenesis. Full article

To assess the therapeutic relevance of BRIP1 in gastric cancer (GC), we examine its functional role in conferring resistance to anoikis within GC cells and elucidate the oncogenic signaling pathways modulated by BRIP1. By integrating the Cancer Genome Atlas (TCGA) and Gene Set Enrichment Analysis (GSEA) databases with Least Absolute Shrinkage and Selection Operator (LASSO) regression, a novel risk score to stratify GC patients based on prognosis was generated, and a significantly differentially expressed gene, BRIP1, was validated through reverse transcription quantitative polymerase chain reaction (RT-qPCR). Protein expression associated with apoptosis, cell cycle, and epithelial-mesenchymal transformation (EMT) was quantified via RT-qPCR and Western blot (WB). 5-Ethynyl-2′-deoxyuridine (EdU) and cell counting kit-8 (CCK-8) assays were conducted to quantify proliferative activity. The protein level in axillary tumor tissues of nude mice was detected by immunohistochemistry (IHC). We established an eight-gene anoikis-related prognostic risk assessment model (DUSP1, VCAN, P3H2, TXNIP, BRIP1, FGD6, GPX3, and RLN2) for GC. Multivariate Cox regression confirmed the risk score as an independent prognostic factor. Among these genes, BRIP1 showed significant differential expression between tumor and normal tissues, as well as normal gastric mucosal epithelial cells and GC cells. Mechanistically, BRIP1 conferred anoikis resistance to GC cells by suppressing the generation of reactive oxygen species (ROS). We found that the PI3K inhibitor LY294002 counteracted BRIP1-driven oncogenic effects, which was evidenced by restored expression of key regulators governing apoptosis, cell cycle progression, and EMT, in addition to suppressed proliferation in GC cells. BRIP1 is postulated to function upstream of the PI3K/Akt signaling cascade. This study establishes a risk scoring model and identifies BRIP1 as a potential prognostic marker for GC. Full article

Oxaliplatin-triggered chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating side effect of cancer treatment that limits the efficacy of chemotherapy and negatively impacts patients’ quality of life dramatically. To better understand the mechanisms of CIPN and to screen for potential therapeutic targets, it is critical to have reliable in vitro assays that effectively mirror the neuropathy in vivo. In this study, we established a dorsal root ganglia (DRG) explant model. This model displayed dose-dependent inhibition of neurite outgrowth in response to oxaliplatin, while oxalic acid exhibited no significant impact on the regrowth of DRG. The robustness of this assay was further demonstrated by the inhibition of OCT2 transporter, which facilitates oxaliplatin accumulation in neurons, largely restoring the neurite regrowth capacity. Using this model, we revealed that oxaliplatin triggered a substantial increase of oxidative stress in DRG. Notably, inhibition of TXNIP with verapamil reduced oxidative stress levels. Our results demonstrated the use of DRG explants as an efficient model to study the mechanisms of CIPN and screen for potential treatments. Full article

Background: Cholestatic liver injury (CLI) is characterized by complex pathogenesis; however, oxidative stress-mediated inflammatory response due to bile acid accumulation in the liver is considered a primary cause. Cynarin (CN), an artichoke phytochemical, has demonstrated different biological activities, including antioxidant and anti-inflammatory ones. The current study aimed to explore the potential hepatoprotective effect of CN on CLI induced by alpha-naphthyl isothiocyanate (ANIT) in mice and investigate the possible involved mechanisms. Methods: Mice received CN (25 and 50 mg/kg) for four consecutive days and were challenged with ANIT (75 mg/kg) once on the second day. Liver injury was examined through biochemical determination of liver injury biomarkers and confirmed by histopathological evaluation. Oxidative stress biomarkers and pro-inflammatory cytokines were detected in the hepatic tissue. RT-PCR, Western blotting, and ELISA were applied to address gene and protein expression of potential underlying molecular targets, including thioredoxin-interacting protein (TXNIP), NLR family pyrin domain-containing 3 (NLRP3) inflammasome, and high-mobility group box 1 (HMGB1). Moreover, nuclear factor kappa-B (NF-κB) activation was determined by immunohistochemical analysis. Results: Our findings revealed that CN remarkably ameliorated ANIT-induced hepatic necro-inflammatory changes and biliary duct injury and restored redox balance in the liver. Mechanistically, CN markedly decreased the expression of TXNIP, NLRP3, active caspase-1, gasdermin D N-terminal (GSDMD-N), interleukin (IL)-1β, and IL-18, which were elevated upon ANIT administration. Moreover, CN suppressed ANIT-induced expression of HMGB1 and NF-κB. Conclusions: Our findings suggest that CN has a protective effect against ANIT-induced CLI in mice that is associated with modulation of the TXNIP/NLRP3 and HMGB1/NF-κB signaling cascades. Full article

Diabetic retinopathy (DR) is a progressive retinal disorder and a leading cause of vision impairment worldwide affecting the livelihood of millions. Its pathogenesis is driven by chronic hyperglycemia-induced neuronal and microvascular injury, leading to capillary occlusion, increased vascular permeability, and the eventual formation of fragile neo vessels. These changes mark the progression from non-proliferative diabetic retinopathy (NPDR) to proliferative diabetic retinopathy (PDR). Diabetic macular edema (DME), characterized by blood–retinal barrier disruption and macular fluid accumulation, further contributes to vision loss. This review provides an integrative perspective on the cellular and molecular mechanisms of DR, highlighting both vascular and neuroglial contributions to retinal pathology. Current therapeutic approaches, including anti-VEGF agents and corticosteroids, offer symptomatic relief but are limited by the need for repeated administration and variability in patient response. Emerging evidence implicates the role of thioredoxin-interacting protein (TXNIP) as one of mediators of the disease progression. Strongly upregulated under hyperglycaemic stress, TXNIP induces oxidative damage, inflammation, and neuronal apoptosis, exacerbating neurovascular dysfunction. We explore potential therapeutic strategies such as gene therapy, TXNIP-targeted molecular interventions, and stem cell-based approaches aimed at achieving long-term modulation of disease mechanisms. This article thus attempts to address a comprehensive understanding of DR pathophysiology and innovative new strategies to improve long-term visual outcomes. Full article