Advanced Glycation End Products Research Articles

Involvement of Mineralocorticoid Receptor Activation by HMGB1 and RAGE in the Development of Acute Kidney Injury.

Although acute kidney injury (AKI) is associated with an increased risk of chronic kidney disease (CKD), the underlying mechanisms remain unclear. High mobility group box-1 (HMGB1), one of the ligands for the receptor for advanced glycation end products (RAGE), is elevated in patients with AKI. We recently demonstrated that the mineralocorticoid receptor (MR) is activated by the RAGE/Rac1 pathway, contributing to chronic renal damage in hypertensive mice. Therefore, this study investigated the role of the HMGB1/RAGE/MR pathway in AKI and progression to CKD. We performed a mouse model of renal ischemia-reperfusion (I/R) with or without MR antagonist (MRA). In vitro experiments were conducted using cultured endothelial cells to examine the interaction between the HMGB1/RAGE and Rac1/MR pathways. In renal I/R injury mice, renal MR activation was associated with elevated serum HMGB1, renal RAGE, and activated Rac1, all of which were suppressed by MRA. Renal I/R injury led to renal dysfunction, tubulointerstitial injury, and increased expressions of inflammation and fibrosis mediators, which were ameliorated by MRA. In vitro, RAGE-aptamer or MRA inhibited HMGB1-induced Rac1/MR activation and upregulation of MCP-1 and NF-κB expressions. 7 days following I/R injury, renal I/R injury mice developed CKD, whereas MRA prevented renal injury progression and decreased mortality rate. Furthermore, in case of MRA treatment even after I/R injury, attenuated renal dysfunction compared to untreated mice was also observed. Our findings suggest that HMGB1 may play a crucial role in AKI and CKD development by activating the Rac1/MR pathway through interactions with RAGE.

Salivary advanced glycated end products, their receptors, and aMMP-8 in periodontitis patients with varying glycemic levels: A cross-sectional study.

Advanced glycation end products (AGE) and their receptors (RAGE) have been implicated in developing periodontal complications in diabetic patients. This study aimed to identify salivary AGE, RAGE, soluble RAGE (sRAGE), and active-matrix metalloproteinase-8 (aMMP-8) levels at varying glycemic levels in periodontitis patients. Ninety-eight participants were categorized into uncontrolled DM-PD group (n=27)-periodontitis patients with uncontrolled Type 2 diabetes mellitus (T2DM) (glycated hemoglobin [HbA1c] ≥7%); controlled DM-PD group (n=33)-periodontitis patients with controlled T2DM (HbA1c 5.7%-6.9%); SH-PD group (n=18)-systemically healthy periodontitis patients; and SH-PH group (n=20)-systemically and periodontally healthy individuals. HbA1c along with the periodontal parameters bleeding on probing (BoP), periodontal probing depth (PPD), clinical attachment loss (CAL), number of missing teeth, and periodontal inflamed surface area (PISA) were estimated. Enzyme-linked immunosorbent assay (ELISA) was used for analyzing salivary AGE, RAGE, sRAGE, and aMMP-8. Multiple linear regression analysis was conducted to develop predictive models for HbA1c based on relevant predictor variables. Periodontitis participants with uncontrolled T2DM exhibited significantly higher BoP, PPD, CAL, number of missing teeth, and PISA, along with elevated AGE, RAGE, and aMMP-8, compared to other groups (p<0.01). A significant positive association was observed between RAGE and HbA1c levels (p<0.01). Among the predictors, BoP (p=0.046) and CAL (p<0.001) demonstrated a significant positive effect on salivary AGE. PPD was positively associated with RAGE (p<0.05), and BoP was negatively associated with salivary sRAGE levels (p=0.038). Salivary biomarkers like RAGE and aMMP-8 exert a potential role in monitoring periodontal health and glycemic control in T2DM patients. Advanced glycation end products (AGE) and their receptors (RAGE) have been implicated in developing periodontal complications in diabetic patients. This study aimed to identify salivary AGE, RAGE, soluble RAGE (sRAGE), and aMMP-8 levels at varying glycemic levels in periodontitis patients. Ninety-eight participants were categorized into Group 1 (n=27)-periodontitis patients with uncontrolled Type 2 diabetes mellitus (T2DM); Group 2 (n=33)-periodontitis patients with controlled T2DM; Group 3 (n=18)-systemically healthy periodontitis patients; and Group 4 (n=20)-systemically and periodontally healthy individuals. Enzyme-linked immunosorbent assay (ELISA) was used for analyzing salivary AGE, RAGE, sRAGE, and aMMP-8. The study revealed that participants with uncontrolled T2DM and severe periodontitis exhibited significantly higher levels of salivary AGE, RAGE, and aMMP-8, along with increased periodontal parameters, compared to controlled T2DM and systemically healthy groups. Conversely, salivary sRAGE levels were significantly lower in the uncontrolled T2DM group. The study also found significant associations between salivary RAGE levels and glycated hemoglobin (HbA1c), as well as between aMMP-8, AGE, and clinical periodontal parameters. The findings of this study highlight the potential clinical utility of salivary biomarkers, particularly RAGE and aMMP-8, as noninvasive diagnostic and monitoring tools to evaluate glycemic control and periodontal health in individuals with diabetes.

Role of the Receptor for Advanced Glycation End Products (RAGE) and Its Ligands in Inflammatory Responses.

Since its discovery in 1992, the receptor for advanced glycation end products (RAGE) has emerged as a key receptor in many pathological conditions, especially in inflammatory conditions. RAGE is expressed by most, if not all, immune cells and can be activated by many ligands. One characteristic of RAGE is that its ligands are structurally very diverse and belong to different classes of molecules, making RAGE a promiscuous receptor. Many of RAGE ligands are damaged associated molecular patterns (DAMPs) that are released by cells under inflammatory conditions. Although RAGE has been at the center of a lot of research in the past three decades, a clear understanding of the mechanisms of RAGE activation by its ligands is still missing. In this review, we summarize the current knowledge of the role of RAGE and its ligands in inflammation.

Evaluation of Advanced Glycation End Products and Malondialdehyde in Type II Diabetes Patients with and without Periodontitis: A Cross-sectional Study

Evaluation of Advanced Glycation End Products and Malondialdehyde in Type II Diabetes Patients with and without Periodontitis: A Cross-sectional Study

Current prevalence of rotator cuff tear in Type 2 diabetes mellitus patients and its association with type of diabetic drug regime (OHA’S vs. insulin therapy) – A prospective study

Background: A prospective study to assess the prevalence of rotator cuff (RC) tears in patients with Type 2 diabetes mellitus. Aims and Objectives: The purpose of this study is to assess the prevalence of RC tear in Type 2 diabetes mellitus patients presenting with shoulder pain to the outpatient clinic. Materials and Methods: A total of 100 diabetic patients with shoulder pain and restriction of movements formed the study group and were prospectively studied using magnetic resonance imaging and were evaluated with regard to the presence of RC tear. The factors that were analyzed included HBA1C levels, duration of diabetes, and type of diabetic medication. All these factors were evaluated with regard to their correlation with RC tear. Results: In our study, we found that the prevalence of RC tear was 37% and there seemed to be a significant correlation between HBA1C levels (P=0.007) as well as prolonged duration of diabetes (P=0.006) with RC tear. It has been established in our study that the occurrence of RC tear is lesser in oral hypoglycemic agents group as compared to insulin group in treating diabetic patients. Conclusion: One independent risk factor for RC tear is diabetes. The prevalence of RC tear is higher in the diabetic population with increased HBA1c levels and prolonged duration of diabetes mellitus. Metformin usage in diabetes mellitus has been associated with reduced incidence of RC tear due to diminished impregnation of advanced glycation end products with in the RC tendon.

Dexmedetomidine Mitigates Acute Lung Injury by Enhancing M2 Macrophage Polarization and Inhibiting RAGE/Caspase-11-Mediated Pyroptosis.

Acute lung injury (ALI) significantly impacts the survival rates in intensive care units (ICU). Releasing a lot of pro-inflammatory mediators during the progression of the disease is a core feature of ALI, which may lead to uncontrolled inflammation and further damages the tissues and organs of patients. This study explores the potential therapeutic mechanisms of Dexmedetomidine (Dex) in ALI. In present study, cecal ligation puncture (CLP)-established ALI model mice and lipopolysaccharide (LPS)-stimulated RAW264.7 cell line were established to discover the influence of Dex. The evaluation of lung injury in vivo using histopathology, TUNEL assay, and analysis of inflammatory factors in bronchoalveolar lavage fluid (BALF) and serum. The receptor for advanced glycation end products (RAGE)/Caspase-11-dependent pyroptosis-related proteins and macrophage polarization markers were analyzed using western blot, immunofluorescence, and flow cytometry. Finally, the mechanism of Dex in macrophages was further verified in vitro. In vivo, Dex alleviated lung injury and decreased TUNEL-positive cell expression in CLP group. Dex decreased tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6 and IL-17A levels in BALF and serum, while increasing IL-10 expression. Dex treatment decreased the protein levels of RAGE, caspase-11, IL-1β and Gasdermin-D (GSDMD) in both in cells and in mice. Dex also down-regulated the synthesis of inducible nitric oxide synthase (iNOS) of classical activation phenotype (M1) markers, and up-regulated the synthesis of CD206 and Arg-1 of alternate activation phenotype (M2) markers. Dex treatment can inhibit inflammation and reduce lung injury caused by CLP. It could be associated with mediating M1 and M2 polarization and suppressing RAGE/Caspase-11-depended pyroptosis.

Pre-diagnostic plasma advanced glycation end-products and soluble receptor for advanced glycation end-products and mortality in colorectal cancer patients.

Advanced glycation end-products (AGEs), formed endogenously or obtained exogenously from diet, may contribute to chronic inflammation, intracellular signaling alterations, and pathogenesis of several chronic diseases including colorectal cancer (CRC). However, the role of AGEs in CRC survival is less known. The associations of pre-diagnostic circulating AGEs and their soluble receptor (sRAGE) with CRC-specific and overall mortality were estimated using multivariable-adjusted Cox proportional hazards regression among 1369 CRC cases in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Concentrations of major plasma AGEs, Nε-[carboxy-methyl]lysine (CML), Nε-[carboxy-ethyl]lysine (CEL) and Nδ-[5-hydro-5-methyl-4-imidazolon-2-yl]-ornithine (MG-H1), were measured using ultra-performance liquid chromatography mass-spectrometry. sRAGE was assessed by enzyme-linked immunosorbent assay. Over a mean follow-up period of 96 months, 693 deaths occurred of which 541 were due to CRC. Individual and combined AGEs were not statistically significantly associated with CRC-specific or overall mortality. However, there was a possible interaction by sex for CEL (Pinteraction = .05). Participants with higher sRAGE had a higher risk of dying from CRC (HRQ5vs.Q1 = 1.67, 95% CI: 1.21-2.30, Ptrend = .02) or any cause (HRQ5vs.Q1 = 1.38, 95% CI: 1.05-1.83, Ptrend = .09). These associations tended to be stronger among cases with diabetes (Pinteraction = .03) and pre-diabetes (Pinteraction <.01) before CRC diagnosis. Pre-diagnostic AGEs were not associated with CRC-specific and overall mortality in individuals with CRC. However, a positive association was observed for sRAGE. Our findings may stimulate further research on the role of AGEs and sRAGE in survival among cancer patients with special emphasis on potential effect modifications by sex and diabetes.

Vitamin D3 Exerts a Neuroprotective Effect in Metabolic Syndrome Rats: Role of BDNF/TRKB/Akt/GS3Kβ Pathway.

Metabolic syndrome (MetS) is usually associated with cognitive impairment, neuropathic pain, and reduced brain-derived neurotrophic factor (BDNF) levels. BDNF via tropomyosin receptor kinase B (TrkB) exerts neuroprotection by activating protein kinase B (Akt) to inhibit glycogen synthase kinase-3β (GSK3β). Although Vitamin D3 (VitD3) has demonstrated favorable metabolic and neuronal outcomes in MetS, the precise molecular mechanisms underlying its neuroprotective effects remain poorly elucidated. We aimed to test the hypothesis that VitD3 mitigates MetS-induced cognition deficits and neuropathic pain via modulating the BDNF/TRKB/Akt/GS3Kβ signaling pathway. MetS was induced in male rats by 10% fructose-supplemented water and 3% salt-enriched diet. After 6 weeks, normal and MetS rats received either vehicle or VitD3 (10 µg/kg/day) for an additional 6 weeks. Glycemic status, lipid profile, and behavioral changes were assessed. The advanced glycation end products (AGEs), and markers of inflammation (TNF-α and NF-κB), oxidative stress (malondialdehyde), and apoptosis (caspase3), as well as BDNF, TrkB, PI3K, Akt, GSK3β, phosphorylated tau, and amyloid beta (Aβ) were assessed in the cerebral cortex. MetS rats had deteriorated glycemic and lipid profiles, higher AGEs, reduced levels of BDNF, TrkB, PI3K, and active Akt, along with increased GSK3β levels, inflammation, oxidative stress, and apoptosis. These changes were associated with higher levels of cognitive impairment markers phosphorylated tau and Aβ, as well as behavioral changes indicative of cognitive impairment and neuropathic pain. VitD3 improved the cognitive and behavioral alterations, while mitigating the associated molecular derangements. Our results indicate that VitD3 may exert neuroprotective effects by modulating the BDNF/TrkB/PI3K/Akt/GSK3β signaling pathway.

Advanced glycation end products (AGEs) involvements in the development of frank Alzheimer’s disease (FAD)

Advanced glycation end products (AGEs) involvements in the development of frank Alzheimer’s disease (FAD)

Measurement of Advanced Glycation End Products (AGEs) Accumulated in Dentin Collagen.

In the Maillard reaction, reducing sugars bind to proteins in a non-enzymatic manner, and the final products are collectively named, advanced glycation end products (AGEs). AGEs accumulate in the human body with age and cause various disorders in tissues and cells. In this study, pentosidine, an AGE that can be stably measured, was used to investigate the differences in pentosidine accumulation within dentin, and whether the results can indicate age. High-performance liquid chromatography was used to measure pentosidine, an AGE that accumulates in dentin collagen, in extracted teeth with no caries and a clear history. The dentin pentosidine concentration increased with age, with a higher pentosidine concentration observed at the enamel-dentin junction aspect than at the pulp cavity aspect. A close correlation was observed between the dentin pentosidine level and age. These findings suggest the utility of measuring accumulation of AGEs in dentin collagen as an indicator of age.

Herbal micelles-loaded ROS-responsive hydrogel with immunomodulation and microenvironment reconstruction for diabetic wound healing.

Persistent inflammation is a major cause of diabetic wounds that are difficult to heal. This is manifested in diabetic wounds with excessive reactive oxygen clusters (ROS), advanced glycation end products (AGE) and other inflammatory factors, and difficulty in polarizing macrophages toward inhibiting inflammation. Berberine is a natural plant molecule that inhibits inflammation; however, its low solubility limits its biological function through cytosis. In this study, we designed F127 micelles to encapsulate berberine with the aim of improving its solubility and bioavailability. Meanwhile, in order to achieve effective drug delivery at the wound site, we designed an injectable ferrocene-cyclodextrin self-assembled oxidation-reactive supramolecular hydrogel drug delivery system. Cellular experiments have shown that the hydrogel can reduce intracellular ROS and AGE production, attenuate cellular damage, promote macrophage polarization toward inhibition of inflammation, and reduce the secretion of inflammatory factors. In an animal model of diabetic mice, this hydrogel dressing reduces the level of inflammation in diabetic wounds, optimizes collagen deposition in diabetic wounds, and ultimately achieves high-quality diabetic wound healing. The work offers a straightforward and effective solution to the challenge of administering hydrophobic anti-inflammatory agents in the context of diabetic wound therapy.

Noninvasive Skin Autofluorescence of Advanced Glycation End Products in Patients with Degenerative Cervical Myelopathy.

To clarify the association between skin autofluorescence of advanced glycation end products (AGEs) and clinical outcomes and pain in patients with degenerative cervical myelopathy (DCM). Consecutive patients with DCM were prospectively enrolled. AGEs assessed by skin autofluorescence (the AGE score) were examined at the middle fingertip in eligible patients. Patients were divided into lower AGE score (AGE-L) and higher AGE score (AGE-H) groups based on a cutoff AGE score of 0.54. Demographic data, laboratory data, maximum spinal cord compression, clinical outcomes, such as European Quality of Life-5 Dimensions, Neck Disability Index, and Japanese Orthopaedic Association score, and Numerical Rating Scale (NRS) score for neck, arm, hand, leg, and foot pain were compared between the two groups. Multiple linear regression analysis was performed to assess the association between the AGE score and the NRS score for pain in the lower limbs. Of the 263 patients, 93 were included in this study (41 with the AGE-L group and 52 with the AGE-H group). Demographic data, laboratory data, maximum spinal cord compression, and clinical outcomes were comparable between the two groups. The AGE-H group had significantly higher NRS scores for leg and foot pain than the AGE-L group. Multiple linear regression analysis revealed that higher AGE scores were significantly associated with more severe pain in the lower limbs in patients with DCM. Noninvasive skin autofluorescence of AGEs may be a useful biomarker for pain symptoms in the lower limbs in patients with DCM.

Zuyangping formula promotes skin wound healing in diabetic rats.

To evaluate the effects of Zuyangping (, ZYP) formula on wound healing in diabetic rats, as well as the molecular mechanisms involved. The main compounds in ZYP formula were identified by the Liquid chromatography-tandem mass spectrometry. Sprague-Dawley rats, injected with streptozotocin (STZ) to establish diabetes model, then, formed a defective skin trauma in the back, and each group was treated with corresponding drugs once a day. Granulation was taken from each time node for histological analysis. The Western blotting was used to measured protein expression of advanced glycation end products receptor (RAGE) and hypoxia-inducible factor-1α (HIF-1α) axis-related proteins. The relative expression levels of inflammatory cytokines and growth factors were measured by the enzyme-linked immunosorbent assay method. The main ingredients were identified in the ZYP formula. Histological analysis showed that the ZYP formula could inhibit the expression of inflammation, promote angiogenesis and collagen deposition. In addition, the ZYP formula could regulate the expression of RAGE and HIF1-α axis-related proteins, thus promoting the wound healing in diabetic rats. The ZYP formula could accelerate wound healing in diabetic rats.

Current Concepts in the Molecular Mechanisms and Management of Diabetic Neuropathy by Pharmacotherapeutics and Natural Compounds.

One of the most crippling effects of diabetes mellitus is diabetic neuropathy, which can cause discomfort, loss of movement, and even amputation. Diabetic neuropathy manifests in a variety of ways, ranging from pain to death. Diagnosing diabetic neuropathy can be challenging since it often goes unnoticed for many years following the onset of diabetes. In addition to oxidative stress in neurons, hyperglycemia activates a number of metabolic pathways that are important sources of damage and possible targets for treatment in diabetic neuropathy. Downstream metabolic cascades caused by prolonged hyperglycemia include activation of protein kinase C, increased production of advanced glycation end products, excessive release of cytokines, increased oxidative stress, and injury to peripheral nerves. Despite the fact that these metabolic anomalies are considered the main cause of diabetes-related microvascular issues, the diverse mechanistic processes of neuropathy are characterized by organ-specific histological and biochemical features. Although the symptoms of diabetic neuropathy can be treated, there are few options to correct the underlying problem. Diabetic neuropathy exerts a tremendous financial, psychological, and physical burden on society, emphasizing the need for efficient and focused treatment. The major goal of this review is to shed light on the multiple mechanisms and pathways that contribute to the onset of diabetic neuropathy and to provide readers with a comprehensive understanding of emerging therapeutic strategies to postpone or reverse various forms of diabetic neuropathy. The article discusses available medications and provides the latest guidelines for the treatment of pain and distal symmetric polyneuropathy, including diabetic autonomic neuropathy, which may help the patients control pain well and assess alternatives for treatment that might be more successful in preventing or delaying the course of a disease.

An Anti-RAGE Chimeric antibody alleviates CCl4-induced liver fibrosis via RAGE/NF-kB pathway in mice

Liver fibrosis is a progressive condition characterized by excessive deposition of extracellular matrix components, leading to organ dysfunction. Chronic inflammation and activation of hepatic stellate cells (HSCs) are two dominant events in all stages of fibrosis development. The receptor for advanced glycation end products (RAGE) pathway is involved in modulating liver injury and fibrosis, and preventing it, or deletion of Ager gene can protect the liver against fibrosis progression. To investigate functions and mechanism of chimeric anti-RAGE monoclonal antibody against liver fibrosis, murine-derived monoclonal anti-RAGE antibodies were used to construct murine-human chimeric antibodies. The properties of the chimeric antibody were characterized, and the biological functions of antibody A5 or its evolved humanized molecule, huA5, were investigated in cell or animal model. The data showed that blocking the RAGE pathway with huA5 robustly reduced liver injury and fibrosis. Furthermore, huA5 significantly suppressed the activation of HSCs and inhibited expression of fibrosis-associated genes, including COL1A1,TIMP1, and ACTA2. huA5 also interfered with RAGE downstream signal transduction and down-regulate both ERK and NF-κB phosphorylation, inhibited the RAGE/NF-kB pathway, leading to reduced expression of pro-inflammatory cytokines and profibrotic markers. Finally, RAGE silencing significantly decreased the expression of activation-related genes in HSCs, inhibiting HSCs proliferation and migration. These results clearly revealed that the anti-RAGE chimeric antibody exerted antifibrotic efficacy in vitro and attenuated liver fibrosis in vivo. HuA5 can be further developed as a lead molecule of drug to treat patients with liver fibrosis.

Gliricidia sepium (Jacq.) Kunth. ex. Walp. leaves-derived biogenic nanohydrogel accelerates diabetic wound healing in rats over 21 days.

This study focused on the potential of Gliricidia sepium (Jacq.) Kunth. ex. Walp. leaves zinc oxide nanoparticles hydrogel (GSL ZnONPs HG) for diabetic wound healing. The major components identified through HPLC analysis in Gliricidia sepium (Jacq.) Kunth. ex. Walp. leaves ethanolic extract (GSL) were apigenin-7-O-glucoside, kaempferol, and protocatechuic acid. These compounds exhibited anti-inflammatory properties. The hydrogel loaded with GSL ethanolic extract and Gliricidia sepium (Jacq.) Kunth. ex. Walp. leaves ethanolic extract zinc oxide nanoparticles (GSL ZnONPs) displayed controlled release and favorable swelling behavior. GSL ZnONPs HG enhanced tissue regeneration, reduced apoptosis, and modulated inflammation in diabetic wounds as demonstrated by wound morphology and closure measurements, as well as histopathological and immunohistochemical evaluations. It is important to highlight the dose-dependent behavior of GSL ZnONPs, demonstrating their effectiveness in promoting diabetic wound healing even at lower concentrations. This was supported by their response to various biomarkers through a significant reduction in vascular cell adhesion molecule-1 (VCAM-1) and advanced glycation end products levels (AGEs), and a notable increase in interleukin-10 (IL-10) and platelet-derived growth factor concentrations (PDGF). Collectively, the study highlights the potential of GSL ZnONPs HG as a promising approach to enhance diabetic wound healing.

Repeated low-intensity noise exposure exacerbates age-related hearing loss via RAGE signaling pathway.

Repeated low-intensity noise exposure is prevalent in industrialized societies. It has long been considered risk-free until recent evidence suggests that the temporary threshold shift (TTS) induced by such exposure might be a high-risk factor for hearing loss. This study was conducted to further investigate the manner in which repeated low-intensity noise exposure contributed to hearing damage. Two-month-old C57BL/6 J mice were exposed to white noise at 96 dB SPL for 8 h per day over 7 days to induce TTS. Auditory brainstem response (ABR) was monitored to assess changes in hearing thresholds, tracking the effects of noise exposure until the mice reached 12 months of age. Our results indicated that noise-exposed mice exhibited accelerated age-related hearing loss spanning from high to low frequencies. Proteomics analysis revealed an upregulation in the receptor for the advanced glycation end-products (RAGE) signaling pathway, which was associated with an activated inflammatory response, vascular injury, and mitochondrial and synaptic dysfunction. Further analysis confirmed increased levels of inflammatory cytokines in the cochlear lymph fluid and significant macrophages infiltration in the cochlear lateral wall, accompanied by hyperpermeability of the blood-labyrinth barrier. Additionally, degenerated mitochondria in the outer hair cells and decreased synaptic ribbons in the inner hair cells were also observed. These pathological changes indicated that noise exposure damages the cochlear cellular components, increasing the cochlear susceptibility to age-related stress. Our findings suggest that TTS caused by repeated low-intensity noise exposure correlates with a severe sensorineural hearing loss during aging; targeting the RAGE signaling pathway could be a promising strategy to mitigate damage from low-intensity noise and slow down the progression of age-related hearing loss.

Human iPSC-based disease modeling studies identify a common mechanistic defect and potential therapies for AMD and related macular dystrophies.

Age-related macular degeneration (AMD) and related macular dystrophies (MDs) primarily affect the retinal pigment epithelium (RPE) in the eye. A hallmark of AMD/MDs that drives later-stage pathologies is drusen. Drusen are sub-RPE lipid-protein-rich extracellular deposits, but how drusen forms and accumulates is not known. We utilized human induced pluripotent stem cell (iPSC)-derived RPE from patients with AMD and three distinct MDs to demonstrate that reduced activity of RPE-secreted matrix metalloproteinase 2 (MMP2) contributes to drusen in multiple maculopathies in a genotype-agnostic manner by instigating sterile inflammation and impaired lipid homeostasis via damage-associated molecular pattern molecule (DAMP)-mediated activation of receptor for advanced glycation end-products (RAGE) and increased secretory phospholipase 2-IIA (sPLA2-IIA) levels. Therapeutically, RPE-specific MMP2 supplementation, RAGE-antagonistic peptide, and a small molecule inhibitor of sPLA2-IIA ameliorated drusen accumulation in AMD/MD iPSC-RPE. Ultimately, this study defines a causal role of the MMP2-DAMP-RAGE-sPLA2-IIA axis in AMD/MDs.

Association between driving pressure, systemic inflammation and non-pulmonary organ dysfunction in patients with acute respiratory distress syndrome, a prospective pathophysiological study.

Driving pressure is thought to determine the effect of low tidal ventilation on survival in patients with acute respiratory distress syndrome. The leading cause of mortality in these patients is non-pulmonary multiorgan dysfunction, which is believed to worsen due to the biological response to mechanical ventilation (biotrauma). Therefore, we aimed to analyze the association between driving pressure, biotrauma, and non-pulmonary multiorgan dysfunction. Additionally, we analyzed this relationship for tidal volume/predicted body weight. Observational study that included adult patients with acute respiratory distress syndrome undergoing invasive mechanical ventilation admitted to the Hospital Clinic of Barcelona, Spain, between June 2019 and February 2021. We conducted mixed-effects models to assess the effects of driving pressure and tidal volume/predicted body weight on the evolution of 22 log-transformed biomarker variables during the first, third, and fifth days after study enrollment. These 22 systemic biomarkers characterized epithelial and endothelial pulmonary dysfunction, inflammation, and coagulation disorders in the included patients. In the same fashion, the association between driving pressure and non-pulmonary multiorgan dysfunction was evaluated by the non-pulmonary sequential organ failure assessment score (non-pulmonary SOFA) and its associated variables. Finally, we performed mediation analyses to assess whether the relationship between biomarkers and driving pressure was mediated by other ventilator-induced lung injury parameters. Thirty-eight patients were included. Driving pressure was independently associated with soluble Receptor for advanced glycation end-products, Interleukin (IL)-8, IL-6, IL-10, IL-17, Interferon-ɣ, Chemokine (C-C motif)-2, Vascular endothelial growth factor, Tissue factor, Protein C, Protein S, and higher dose of norepinephrine. However, this relationship attenuated over time. In contrast, tidal volume/predicted body weight was not associated with any of the 22 biomarkers tested . A concomitant increase in positive end-inspiratory plateau pressure or tidal volume did not mediate the effect of driving pressure on biomarkers. Conversely, the association between compliance of the respiratory system and pulmonary epithelial dysfunction was primarily mediated by driving pressure. Driving pressure, but not tidal volume/predicted body weight, was correlated with epithelial and endothelial pulmonary dysfunction, inflammation, coagulation disorders, and hemodynamic dysfunction. However, this relationship diminished over time.

MUSA PARADISIACA (KADALI) PSEUDOSTEM AS A POTENT NUTRACEUTICAL IN KIDNEY DISORDERS- A REVIEW

Musa paradisiaca, is a tropical plant widely recognized for its nutritional and medicinal properties. While the fruit is celebrated for its carbohydrate-rich composition and essential vitamins, the pseudostem-often treated as agricultural waste-has garnered attention for its remarkable therapeutic potential. This review compiles and critically analyzes current evidence on the pharmacological effects of the banana pseudostem, emphasizing its role as a nutraceutical in managing diseases such as urolithiasis, diabetes, and nephropathy. The pseudostem exhibits anti-inflammatory, diuretic, anti-urolithiatic, and nephroprotective properties, with studies demonstrating its ability to reduce stone-forming markers, such as glycollic acid oxidase and lactate dehydrogenase, while preventing kidney stone deposition. In diabetes management, the pseudostem shows anti-hyperglycemic effects by modulating advanced glycation end-products and improving kidney function, positioning it as a potential plant-based alternative for diabetic nephropathy. Furthermore, its nutraceutical applications extend to the development of functional foods and supplements, leveraging its rich nutritional profile of carbohydrates, fiber, protein, and essential minerals. By transforming the pseudostem from an underutilized byproduct into a valuable resource, Musa paradisiaca offers sustainable solutions for healthcare and agriculture. This review underscores the pseudostems potential in Ayurveda medicine, advocating its inclusion in dietary regimens and therapeutic formulations to address chronic conditions effectively.